Aryl ketals of polycyclic oxo compounds and processes

ABSTRACT

THE INTERMEDIATES AND PROCESSES OF THIS DISCLOSURE PROVIDE A NEW STEREO-SPECIFIC TOTAL SYNTHESIS OF STEROIDAL MATERIALS HAVING KNOWN VALUABLE PHARMACOLOGICAL PROPERTIES. A FUNDAMENTAL FEATURE OF THIS DISCLOSURE IS THE UTILIZATION OF ARYL KETALS, PREFERABLY PHENYLENEDIOXY KETALS DERIVED FROM CATECHOL AS PROTECTIVE GROUPS FOR OXO MOIETIES IN THE POLYCYCLIC INTERMEDIATES USED IN THE AFORESAID TOTAL SYNTHESIS.

United States Patent 3,708,500 ARYL KETALS OF POLYCYCLIC OX0 COMPOUNDSAND PROCESSES Michael Rosenberger, Bloomfield, and Gabriel Saucy, EssexFells, N.J., assignors to Hoffmann-La Roche Inc., Nutley, NJ.

No Drawing. Continuation-impart of applications Ser. No. 824,319, May13, 1969, now Patent No. 3,544,600, and Ser. No. 825,389, May 16, 1969,now abandoned. This application Feb. 12, 1970, Ser. No. 11,023

Int. Cl. C07d 13/10 US. Cl. 260-3405 11 Claims ABSTRACT OF THEDISCLOSURE The intermediates and processes of this disclosure provide anew stereo-specific total synthesis of steroidal materials having knownvaluable pharmacological properties. A fundamental feature of thisdisclosure is the utilization of aryl ketals, preferably phenylenedioxyketals derived from catechol as protective groups for 0x0 moieties inthe polycyclic intermediates used in the aforesaid total synthesis.

Related applications This application is a continuation-in-part ofcopending U.S. application Ser. No. 824,319, filed May 13, 1969, now US.Pat. 3,544,600, and Ser. No. 825,389, filed May 16, 1969, now abandoned.

Detailed description of the invention This invention is concerned withcertain polycyclic compounds and with processes for their synthesis.More particularly this invention relates to novel derivatives ofcyclopenta[f] 1]benzopyrans and 7H-naphtho[2,1-b]- pyrans, and tomethods for their production. These compounds are useful asintermediates in syntheses of steroids and D-homosteroids, respectively.In syntheses of steroidal materials steric considerations are of greatsignificance. The most used steroidal compounds are those having aC/D-trans ring junction with the substituent in the 13- position beingin the B-stereoconfiguration. The present invention provides a faciletotal synthesis of 13B-C/D- trans-steroidal materials. This desirableresult is obtained via a unique asymmetric induction with opticalspecificity preserved in subsequent reaction steps. A particular aspectof this invention resides in the use of arylenedioxy ketals asprotective groups for intermediate compounds in the synthesis ofsteroids. Arylenedioxy ketals exhibit unexpected advantages over otherketal protective groups, e.g., alkylenedioxy ketals in that the formergroups are more stable to the reaction conditions employed in thesynthesis thus providing substantially higher yields of desired endproducts. This is particularly true in the case of steps requiringoxidation in the presence of acid.

In a major aspect, this invention is concerned with novel derivatives ofcyclopenta[f][1] benzopyrans having the tricyclic nucleus and novelderivatives of naphtho[2,1-b]pyrans having the tricyclic nucleus3,708,500 Patented Jan. 2, 1973 ice These novel compounds are generallydefined by the formula:

B is the remaining residue of an aryl group which may be monocyclic orbicyclic and which may bear one or more additional substituents selectedfrom the group consisting of lower alkyl and lower alkoxy; R is aprimary alkyl group of from 1 to 5 carbon atoms; R is hydrogen lowerprimary alkyl, or lower acyl; R 1, R12, R and R are each independentlyhydrogen or lower alkyl; Z is carbonyl or a group of the formula R ishydrogen or lower acyl; R is hydrogen or lower aliphatic hydrocarbyl; Trepresents either a single or a double bond; U represents a single or adouble bond and is a single bond when T is a single bond; m is aninteger having a value of 1 to 2; n is an integer having a value of from0 to 1 and is 0 when T represents a double bond and is 1 when Trepresents a single bond; r is an integer having a value of from 0 to 1and is 0 when T is a double bond and 1 when T is a single bond; and s isan integer having a value of from 0 to l and is 0 when U is a doublebond and 1 when U is a single bond.

As used throughout the specification and appended claims, the termhydrocarbyl group denotes a monovalent substituent consisting solely ofcarbon and hydrogen the term hydrocarbylene denotes a divalentsubstituent consisting solely of carbon and hydrogen and having itsvalence bonds from different carbons; the term aliphatic, with referenceto hydrocarbyl or hydrocarbylene groups, denotes groups containing noaromatic unsaturation, but which can be otherwise saturated orunsaturated, i.e., an alkyl or alkylene, or an aliphatic groupcontaining olefinic or acetylenic unsaturation; the term alkyl groupdenotes a saturated hydrocarbyl group, whether straight or branchedchain; the term primary alkyl group denotes an alkyl group having itsvalence bond from a carbon bonded to at least two hydrogens; the termfalkoxy denotes the group R'O, where R' is alkyl; the term acyl groupdenotes a group consisting of the residue of a hydrocarbylmonocarboxylic acid formed by removal of the hydroxyl portion of thecarboxyl group; the term oxyhydrocarbyl denotes a monovalent saturatedcyclic or acyclic group consisting of car bon, hydrogen, and oxygencontaining only one oxygen in the form of an ether linkage; and the termlower as applied to any of the foregoing groups denotes a group having acarbon skeleton containing up to and including eight carbons, such asmethyl, ethyl, butyl, tertAbutyl, hexyl, Z-ethylhexyl, vinyl butenyl,hexenyl, ethinyl, ethylene, methylene, formyl, acetyl, Z-phenylethyl,benzoyl, methoxymethyl, l-methoxyethyl, tetrahydropyran-Z-yl, methoxy,ethoxy, and the like.

In the formulas presented herein the various substituents on cycliccompounds are joined to the cyclic nucleus by one of three notations, asolid line indicating a substituent which is in the fl-orientation(i.e., above the plane of the paper), a dotted line indicating asubstituent which is in the tat-orientation (below the plane of thepaper), or a. wavy line, M-) indicating a substituent which may be ineither the aor [3- orientation. The position of R has been arbitrarilyindicated as the B-orientation, although the products obtained in theexamples are all racemic compounds unless otherwise specified.

Preferred compounds are those wherein Y is 3,3- (arylenedioxy)butylwherein the arylenedioxy group, when taken with the 3-car=bon of thebutyl radical, forms a dioxolane ring system, especially 3,3-(phenylenedioxy)- butyl, 3,3-(2,3-naphthalenedioxy)-butyl and3,3(4,5-dimethylphenylenedioxy)-butyl; R is n-alkyl, especially methyland ethyl; and, when s has a value of 1, the 911- (when m is l) orlOa-(when m is 2) hydrogen is transoriented with respect to R Subgenericto the tricyclic compounds of Formula I are the 3-substituted6a,8-alkyl-l,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyrans byalternate nomenclature 3-substituted-6aB-alkyl 2,3,5,6a,8 hexhydrolH-cyclopenta[f] [l]-benzopyrans) and the3-substituted-6ap-alkyll,2,5,6a,7,8,9 octahydro 3H-naphtho[2,l-b]pyrans(by alternate nomenclature 3-substituted-6a,8-alkyl-l,2,3,5,6, 621,8,9octah'ydro-7H-naphtho[2,1-b]pyrans), hereinafter referred to as dienes,having the formula:

wherein R1, R Z, Y and m are as defined above; the 3- substituted 6a]?alkyl-1,2,3,5,6,6a,7,9,9,9a-decahydrocyclopenta [f] [1]benzopyrans (byalternate nomenclature 3 substituted6a/3-alkyl,2,3,5,6,6a,8,9,9a-octahydro-1H- cyclopenta[f] [1]benzopyrans)and the 3-substituted- 6215 alkyl 1,2,5,6,6a,7,8,9,l0,la decahydro 3H-naphtho[2,l-b]pyrans (by alternate nomenclature 3-substituted 6a,? alkyl1,2,3,5,6,6a,8,9,10,10a-decahydro- 7H-naphtho[2,l-b]pyrans), hereinafterreferred to as monoenes represented by the formula:

H YCHZ k/ RH wherein R R R Z, Y, and m are as defined above; and the3-substituted-6afi-alkyl-4a-hydroxyperhydrocyclopenta[f][l]benzopyransand the 3-substituted-6a 8-alkyl- 4ahydroxyperhydro-3H-naphtho[2,l-b]pyrans and their lower alkyl ethers andmonoacyl esters, hereinafter ferred to as perhydro compounds,represented by the formula:

2 mokf EH1) wherein R R R11, R12, Z, Y and m are as defined above.

This invention is concerned wtih a method for producing the compounds ofFormula I via the following general reaction scheme:

R1 0 0v R n 0 l4 A: l I! Yemen H ncrnocn=cm Hm wherein Y, R R R R Z, andm are as defined above; and V is hydrogen, lower alkyl or lower acyl.

Thus, the process of this invention comprises the general steps of (l)condensation of a substituted 7-hydroxy- 1-alken-3-one or a variantthereof (II), as defined below, with a 2-alkylcycloalkane-1,3-dione(III), as defined below, to produce diene (Ia); (2) saturation of the9,9aor l0,l0a-double bond of diene (Ia) to produce monoene (Ib); and (3)introduction of a hydroxy, alkoxy, or acyloxy group at the 4a-positionand a hydrogen atom at the 9bor IOb-position of monene (Ib) to produceperhydro compound (Ic). It is to be understood that the foregoingreaction sequence is merely schematic in nature, and that each depictedstep can represent only one or Irlnore than one reaction, as will bemore fully described erein.

1-al'ken-3-one compounds of Formula II are employed as one of thestarting materials for the foregoing reaction sequence. Illustrativeexamples of these 1-alken-3- ones include the11,11-arylenedioxy-7-hydroxy-l-alken-3- ones, preferably11,11-phenylenedioxy-7-hydroxy-l-dodecen-3-one.

The 11,11-arylenedioxy-7-hydroxy-1-dodecen-3-ones of Formula II above orcyclic variations thereof are readily synthesized from4,4-ethylenedioxy-l-chloropentane as per the following reactionsequence:

where B is as above, C is alkylenedioxy, preferably ethylenedioxy orarylenedioxy, preferably phenylenedioxy, X is a halide, preferablychloride, R is as hereinafter described and R is lower alkyl.

As indicated in the above sequence in one embodiment 4,4-alkyleneorphenylenedioxy-lchloropentane (a) is converted to the Grignard bytreatment with magnesium metal. This reaction may be activated by theaddition of a crystal of iodine to the reaction medium. The Grignard isthen reacted with glutaraldehyde (b) to yield a hemiacetal (c).Conversion of this hemiacetal to Formula II compounds may beaccomplished by alternative routes. In a first route, where C is B, thehemiacetal (c) is reacted with vinyl Grignard in an ethereal solvent,e.g., tetrahydrofuran at 20 to 10 C. to yield the vinyl hydroxy compound(g). Treatment of (g) With manganese dioxide and R H at room temperaturein a hydrocarbon solvent yields compounds of Formula II.

The hemiacetal (c) may also be oxidized utilizing a chemical oxidizingagent, e.g., silver nitrate, bromine, so-

dium dichromate bihydrate or potassium dichromate to yield the lactone(d). It is preferable that when the ketal moiety C is arylenedioxy thatthe OXidiZing agent used be other than bromine due to the possibility ofbromination of the aromatic ring. It is also possible to oxidize thehemiacetal (c) catalytically using oxygen and a noble metal catalyst,e.g., platinum black. Where C is arylenedioxy in lactone (d), thelactone may be converted directly to compounds of Formula II by reactionwith vinyl Grignard in ethereal solvent, e.g., tetrahydrofuran attemperatures below 0, preferably 70" C. to -45 C.

Where 'C in lactone d) is alkylenedioxy, the lactone is treated withaqueous acid to hydrolyze the ketal group to form the keto lactone (e).Treatment of the keto lactone with the desired dihydroxy aryl compoundsuch as, for example, catechol, 4,5-dimethylcatechol or a 1,2 or2,3-naphthdio1, prefrably in an inert organic solvent, e.g., an aromatichydrocarbon such as benzene, toluene or xylene, preferably benzene underconventional conditions, e.g., at reflux.

The aforesaid ketalization reaction may produce a ketal half-ester as anintermediate which is readily convertible into the desired arylenedioxylactone upon distillation.

Compounds of Formula II are then obtained from said arylenedioxylactones (f) by the selective addition of vinyl Grignard, e.g., vinylmagnesium chloride to the lactone at low temperatures, e.g., below 0 C.,most preferably at about 45 C. in an inert organic solvent medium suchas an etheric solvent, preferably diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane or the like.

In an alternative procedure, ketal lactones of Formula d wherein C is Bmay be conveniently prepared from the arylenedioxyketal (h) by reactionwith a S-oxo-pentanoic acid ester, e.g., the ethyl ester at atemperature of about 60 C. to 30 C. in tetrahydrofuran.

Because of the susceptibility of the vinyl group of the7-hydroxy-1-alken-3-one to decomposition, it is desirable, although notessential, that this compound be converted to more stable variants, suchas those of the formula:

R12 Ha wherein R R Y and V are as defined above; and R is chloro,hydroxy, lower alkoxy, lower hydrocarbylamino or di(lowerhydrocarbyl)amino.

As exemplary, these compounds of Formula Ila are readily produced fromthe vinyl ketones of Formula II by known techniques. For example,1-chloro-7-hydroxyalkan-3-ones are obtained by the anti-Markownikotfreaction of the vinyl compound with hydrogen chloride in known manner.l-hydroxy and l-alkoxy derivatives are obtained by the base-catalyzedreaction of water or a lower alkanol, for example, methanol, with thevinyl ketone. Additional derivatives are formed by the reaction of thevinyl ketone with a mono(lower hydrocarbyl)- or di(lowerhydrocarbyl)-amine to form the Mannich base l-(lower hydrocarbyl)aminoor1-di(lower hydrocarbyl) amino-7-hydroxyalkan-3-one. A particularlyadvantageous procedure is to oxidize a hydroxy vinyl compound e.g.Formula g with manganese dioxide in the presence of such an amine. Insome instances, particularly in large scale commercial operation, it maybe desirable to convert the Mannich base to its crystalline acidaddition salts, particularly quaternary ammonium salts. All of thechloro, hydroxy, alkoxy, and aminoalkanones yield the alkenones ofFormula II under the conditions of the condensation with the2-alkylcycloalkane-1,3-dione.

The compounds of Formula II as is evident from the previously describedreaction sequence can be used in the form of still another variant. Thisis the cyclized variant comprising a cyclic hemiketal, i.e.,Z-tetrahydropyranol of the formula:

H -Rn wherein Y is as defined above and R is lower hydrocarbylamino ordi(lower hydrocarbyl)amino.

The variants of Formula IIb can be prepared from compounds of Formula IIby reaction with the same reactants as are used to produce thosecompounds of Formula IIa wherein R is lower hydrocarbylamino or di(lower hydrocarbyl)amino. As is apparent, those compounds of Formula IIawherein R has the aforesaid meanings and the compounds of Formula IIbare isomers. These isomers exist in the form of a ketone of Formula IIaor in the form of the cyclic hemiketal of Formula IIb or as anequilibrium mixture of the two forms. Whether a particular Mannich baseof Formula IIa exists in that form or the hemiketal form or in anequilibrium mixture consisting primarily of one or the other will dependupon the environmental conditions in which it is placed, such astemperature, solvent, and pH of reaction medium, as well as theparticular meaning of Y and R or R Either form is useful for thepurposes of this invention since these isomers are used in a reactionwith compounds of Formula III, infra, and either the acyclic form ofFormula Ila or the cyclic hemiketal form of Formula 11b is useful forthis purpose. A particular advantage of the cyclic form is its greaterstability as compared with the acyclic form and also as compared withthe vinyl ketones of Formula II. In order to obtain the cyclic form itis essential that in the compound of Formula IIa, V is hydrogen. Acidicconditions shift the equilibrium away from the cyclic form. Use of anoptically active amine, e.g., a-phenylethylamine, offers the advantageof resolving the compound, for example, via salt formation, e.g., theoxalate salt, to give an optically pure isomer of Formula IIa or IIbwhich is then used either in the form of the'free base, as the salt oras a lower alkanol adduct, e.g., methanol adduct in the remainder of thereaction sequence of this invention and when coupled with the uniqueasymmetric induction and preservation of optical specificity thereofoffers a facile route to optically pure steroidal materials.

As is indicated above, the 7-hydroxy group of the 7- hydroxy-dodecanoneof Formula II or IIa can be esterified or etherified for thecondensation reaction with the cycloalkanedione. These reactions can beeffected in known manner. For example, the 7-hydroxyalkan-3-one can bereacted with a carboxylic acid or an acid chloride to produce an ester,or can be converted to an ether by either (1) preferably, known acidcatalyzed etherifications, e.g., with isobutylene or dihydropyran or (2)conversion of the 7-hydroxyalken-3-one to its sodium salt followed byreaction of the salt with an alkyl halide. In the event R is hydrogen,this hydroxyl group is also etherified or esterified.

The starting material of Formula II or variant thereof can either beused in racemic form or in optically active form. When used in opticallyactive form, the 7S-antipode is preferred for reasons more fullyexplained below.

The second reactant employed in the condensation as generally mentionedabove is a 2-(lower alkyl)cycloalkane-l,3-dione of the formula:

8 These compounds are known compounds and description of their synthesisis accordingly unnecessary. Suitable componds includeZ-methylcyclopentane-1,3-dione, Z-ethylcyclopentane-1,3-dior1e,Z-propylcyclopentane- 1, 3-dione, 2-butylcyclopentane-1,3-dione,Z-methylcyclohexane-1,3-dione, and the like.

The conditions for the condensation of ketone (II) or variant (IIa orIIb) with cyclic dione (III) are not narrowly critical, although it ispreferred, particularly when the acyclic ketone is charged as the vinylketone, that a non-oxidizing atmosphere, e.g., nitrogen or argon, beemployed. It is further preferred that an antioxidant, for example,phenolic compounds such as hydroquinone, be present. Furthermore, thereaction can be conducted in the absence or presence of acid or basepromoters. Suitable basic promoters include those heretofore known topromote the Michael condensation, including inorganic bases, forexample, alkali metal hydroxides, such as sodium hydroxide or potassiumhydroxide, and organic bases, including alkali metal alkoxides, forexample, sodium or potassium methoxide or ethoxide, and ammoniumhydroxides, particularly benzyltrialkylammonium hydroxide. A preferredclass of base promoters are the amines, especially tertiary amines andmost preferably pyridinetype compounds such as pyridine and thepicolines. Acid promoters which can be employed include organiccarboxylic acids such as acetic acid or benzoic acid; organic sulfonicacids such as p-toluenesolfonic acid; and mineral acids such as sulfuricacid, phosphoric acid, hydrochloric acid, and the like. The amount ofpromoter employed is not narrowly critical and can vary from catalyticamounts to molar amounts.

The ratio of ketone (II) or variant (IIa or 11b) to cyclic dione (III)is not narrowly critical, although approximately equimolar amounts arepreferred. Although there is no particular advantage to the use ofexcesses of either reactant, the cycloalkanedione can be more readilyemployed in excess because, due to its general low solubility in knownorganic solvents, unreacted cycloalkanedione can be easily recoveredfrom the reaction mixture.

The reaction temperature is not critical and can vary from roomtemperature or below to reflux temperature or higher. The condensationis preferably conducted in the presence of an inert solvent to insure afluid reaction mixture and uniform reaction temperatures. Suitablesolvents include tertiary alcohols such as tert.-butanol; aliphatic andaromatic hydrocarbons such as cyclohexane, hexane, octane, benzene,xylene, toluene, and the like; ethers such as diethyl ether,tetrahydrofuran, and the like; chlorinated hydrocarbons such as carbontetrachloride, chloroform, and the like; as well as dipolar aproticsolvents such as dimethyl sulfoxide and the N,N-disubstituted amidessuch as dimethylformamide or dimethylacetamide.

The product of the condensation, depending upon the nature of vinylketone or variant (II, IIa or IIb) and/or the reaction promoteremployed, can be one or more of CHzY VI YCHQIVWK/WR" n Ia-l wherein R RR V, Y, and m are as defined above.

When vinyl ketone (-11) is a 7-alkoxyor 7-acyloxy compound, the productwill be a compound of Formula IV. However, when the vinyl ketone is a7-hydroxy compound, or the reaction conditions are sufficient to converta 7-alkoxyor 7-acyloxy group, if present, the product will depend uponthe promoter.

When the promoter is an acid or a relatively weak base, such aspyridine, or when no promoter is employed at all, the reaction productobtained from the 7-hydrofxy vinyl ketone is the diene, i.e., tricyclicenol ether la-4). When a strong base, such as sodium or potassiumhydroxide, is employed as a promoter, a crystalline product having theFormula V1 is isolated, although compounds of Formulae IV and V are alsopresent in the reaction mixture. However, the compounds of Formulae IV,V and VI, upon treatment with an acid, such as acetic acid,para-toluene-sulfonic acid, or sulfuric acid, readily form the diene,i.e., tricyclic enol ether (Ia-l). It should also be noted that theconversion of the acyloxy or alkoxy groups of compound (IV) to a hydroxygroup in an acidic medium is accompanied by cyclization to enol etherla-1).

The condensation of a vinyl ketone of Formula II or a variant thereof ofFormula Ila or IIb with a cycloalkanedione of Formula III is one of thekey features of this reaction. It is in this condensation that specificstereochemical induction at one member of the critical C/D-ringjunction. of the eventual steroidal product occurs. 'lhus, thisinvention is particularly advantageous in that it involves a uniqueasymmetric induction. Thus, the products of the condensation, i.e., the'dienones of'Formula la-l, have at least two asymmetric centers atpositions 3 and 6a permitting theoretically of two racemates or fouroptical antipodes. However, as a result of the condensation of thisinvention, when using a racemic starting material of Formula II, IIa or[[Ib wherein R and R are both hydrogen only a single racemate of FormulaIa-l results and when using an optically active starting material ofFormula II, Ila or 1% wherein R and R are both hydrogen only a singleoptical antipode of Formula Ia-1 results. It has further been found thatwhen starting with a compound of Formula II or Ila with a7S-stereoconfiguration or of Formula Ilb with correspondingstereoconfiguration there is obtained the more desirable opticalantipode of Formula Ia-l having a 6aB-stereoconfiguration. Thus, toprepare steroidal materials having the more desiredl3B-stereoconfiguration by the synthesis of this invention one caneither start with the antipode of Formula II, Ila or IIb, which can beprepared by resollving a racemic compound of Formula II, Ila or I' Ib,or one can resolve at some intermediate stage subsequent to thecondensation with a cycloallkanedione of Formula III or one can resolvethe end-product steroidal material.

In any event, the unique asymmetric induction concurrent to thecondensation of this invention renders the obtention of a single opticalantipode as an end-product more facile. The simultaneous formation ofthe dienol ether of Formula Ia1 with unique asymmetric induction is aspecial advantage of this invention.

The dienes of 'Formula Ia in the presence of water and acid, e.-g.,sulfuric acid in acetone, aqueous acetic acid or aqueous hydrochloricacid in dioxane, undergo acid hydrolysis to form indenones of theformula 0 Y I HOl MNR wherein R1, R R Y and m have the same meaning asabove.

The indenones of Formula Ia are themselves convertible to compounds ofFormula -Ia via dehydration, for example, via acid catalyzed azeotropicdistillation in benzene. Suitable acid catalysts are p-toluenesulfonicacid, potassium bisulfate, boron trifluoride etherate and the like. Thisreversible hydrolysis of compounds of Formula la is useful in theirpreparation and purification. Thus, in instances where the directpurification of compounds of Formula la is difiicult it is often morefacile to hydrolyze the compound of Formula. Ia to a compound of FormulaIa, which can then be purified, for example, by chromatography, andsubsequently be reconverted to the desired compound of Formula Ia viadehydration.

The ketodienes of Formula Ia-l are readily converted to thecorresponding 7B-alcoho1s and their esters as represented by theformula:

R 12 Ia-2 wherein Y, R R R R and m are as previously defined; by thesequence of reactions comprising reduction of the ketone to the alcoholand, if desired, subsequent esterification.

The reduction can be eifected by any of the known methods for thechemical reduction of a ketone, e.g., by reaction of dienone (Ia-1) withan alkali metal or Group III-metal reducing agent. By the term. alkalimetal, as employed herein, is meant a Group I-metal having an atomicnumber of from 3 to 19, inclusive, i.e., lithium, sodium, and potassium.Group III-metals include those having atomic numbers of from 5 to 13,inclusive, i.e., boron and aluminum. Illustrative examples of thesereducing agents include an alkali metal, preferably lithium or sodium,in liquid ammonia or a liquid aliphatic amine; tri(loweral1koxy)-aluminum compounds such as triisopropoxyaluminum; di(lowera1.kyl)-aluminum hydrides such as diethylaluminum hydride anddiisobutyl-aluminum hydride; alkali metal-Group III-metal complexhydrides such as lithium aluminum hydride, sodium aluminum hydride, andsodium borohydride; tri(lower alkoxy)a1kali metal-Group III-metalcomplex hydrides such as trimethoxy lithium aluminum hydride andtributoxy lithium aluminum hydride; diisobutyl aluminum hydride and thelike. The alkali metal-Group III-metal complex hydrides are preferred asreducing agents, with 11 the nonalkaline reagents, such as lithiumaluminum hydride, being especially preferred.

This reaction is effected in any suitable inert reaction medium, such ashydrocarbons, e.'g., cyclohexane, benzene, toluene, and xylene; ethers,e.g., diethyl ether, diisopropyl ether, and tetrahydrofuran. Proticsolvents, such as water or alcohols, should not be employed when lithiumaluminum hydride is the reducing agent, but can be employed with sodiumborohydride.

The remaining reaction conditions are not narrowly critical, although itis generally preferred to effect the reduction at reduced temperatures,i.e., below about room temperature (about 2025 C.). Temperatures in therange of from about C. to about room temperature are normally employed.

The free alcohol is recovered from the reaction mixture after treatmentof the mixture with acid. The alcohol can be esterified in known manner,for example, by basecatalyzed reaction with a carboxylic acid halide orcarboxylic acid anhydride. Illustrative bases include inorganic basessuch as sodium hydroxide and potassium hydroxide and organic bases suchas a sodium alkoxide or an amine, especially a tertiary amine, and moreparticularly, pyridine and the picolines.

The ketodienes of Formula Ia-l can also be converted to their7,8-hydroxy-fiat-hydrocarbyl derivatives represented by the formula:

wherein R is as previously defined and X is a halogen having an atomicnumber of from 17 to 35, inclusive (i.e., chlorine or bromine).

This Grignard reaction is conducted in known manner. For example, theGrignard reagent is prepared by reacting a hydrocarbyl halide withmagnesium in an ether reaction medium, for example, ethyl ether ortetrahydrofuran, at elevated temperatures, generally in the range offrom about 40 C. to about 75 C. The ketodiene (Ia-1) is then added tothe Grignard solution at about room temperature, although higher orlower temperatures can be employed. The resulting reaction product ishydrolyzed to produce the free alcohol, which can be esterified asdiscussed above.

Alternatively, the alcohols can be prepared by reaction of ketodiene(Ia-1) with a hydrocarbyl alkali metal compound such as methyl lithium,sodium acetylide, potassium acetylide, and the like.

The second step of the general synthesis of the tricyclic compounds ofthis invention comprises conversion of the dienes of Formula Ia to themonoenes of Formula Ib by catalytic hydrogenation. Suitable catalystsinclude the noble metals, such as platinum, palladium, rhodium, and thelike, as well as Raney nickel and other hydrogenation catalysts. Thesecatalysts can be employed in the form of the metal alone, or can bedeposited on suitable support materials, such as carbon, alumina,calcium carbonate, barium sulfate, and the like. Palladium and rhodiumare preferred as catalysts. The hydrogenation is preferably conducted inthe presence of inert solvents such as hydrocarbons, alcohols, ethers,and the like. The reaction conditions of pressure and temperature arenot narrowly Ila-3 critical, and normally a hydrogen pressure of aboutone atmosphere and a temperature of about room temperature are employed.These ambient conditions are generally preferred to avoid significanthydrogenation of the 4a,9b(10b)-double bond, although more severeconditions, for example, up to about C. and up to about 100 atmospheres,can be employed if desired. The hydrogenation medium can be acidic,neutral, or basic, as may be desired, although neutral media, such ashydrocarbons, e.g., toluene or hexane, or basic media, such as analcohol-base, e.g., methanol-sodium hydroxide, mixture are preferred forbest results. In general, hydrogenation of the diene of Formula Ia leadsto the corresponding monoene of Formula Ib. However, in the event R isan unsaturated hydrocarbyl radical, the hydrogenation, in addition tohydrogenating the ring double bond, also hydrogenates the 7a-hydrocarbylsubstituent, converting it to an alkyl group.

Via the aforesaid catalytic hydrogenation C/D-trans compounds are formedin a major proportion when bydrogenating a diene of Formula Ia-2. Thismethod thus provides an advantageous synthesis of C/D-trans steroidalmaterials. When hydrogenating a diene of Formula Ia-l, C/D-cis compoundsare formed in a major propor tion. This method thus provides anadvantageous synthesis of C/D-cis steroidal materials.

Compounds wherein Z is carbonyl, as represented by the formula:

H YCHz UNWR R 12 Ib-l wherein Y, R R R and m are as previously defined;can be converted to the corresponding alcohols or esters of the formula:

H YCH2- b Ru wherein Y, R R R R and m are as previously defined; or tothe 7B-hydroxy-7tit-hydrocarbyl compounds of the formula:

LII

2 R12 Ill-3 wherein Y, R R R R R and m. are as previously defined; bythe techniques discussed above regarding the dienes of Formula Ia.

When Z is carbonyl and the hydrogenation is effected under basicconditions, there is a tendency toward the production of predominantlythe 6a/9a(l0a)-cis-compound; that is, the hydrogen atom in the 9a(l0a)-position of Formula Ib-l is predominantly in the [Si-orientation.

When these compounds are intended as intermediates for the synthesis ofsteroids having the C/D-trans-orientation, this technique is notparticularly desirable. Although the ratio of pto tit-orientation fallsto about 1:1 at neutral conditions when hydrogenating a compound whereinZ is carbonyl, it is preferred to hydrogenate a 7fl-alcohol or ester ofFormula Ia-2 because the products of this hydrogenation arepredominantly the 6a/9a(10a)-trans-compounds. Compounds of Formula Ia-3when subjected to the hydrogenation yield a ratio of 5- totit-orientation in between that of the compounds of Formula Ia-l andthat of the compounds of Formula Ia-2. When monoenes of Formula Ib-1having C/D-trans-configuration are desired, it is preferable to firstreduce the dienone of Formula Ia-l to a corresponding hydroxy compoundof Formula Ia-2 prior to the catalytic hydrogenation. Following thecatalytic hydrogenation the carbonyl moiety in Formula Ib-1 can beregenerated by conventional means, such as oxidation with CrO Themonoene compounds of Formula Ib prepared by the above-describedhydrogenation contain at least three asymmetric centers, at positions 3,6a and 9a when m is one and at positions 3, 6a and 10a when m is two.With respect to these three centers there are thus eight antipodalconfigurations possible. By virtue of the unique asymmetric induction ofthis invention, proceeding from a racemic starting material of FormulaII, IIa or 1113 only four of these antipodes of Formula Ib are preparedand proceeding from an optically active starting material of Formula II,Ila or IIb only two of these antipodes of Formula Ib are prepared.Moreover, by the above-described hydrogenation of this invention and byappropriate selection of the 7-substituent in the diene of Formula Iasubjected to the hydrogenation there can predominantly be prepared the.desired 6a,9a-(10a)-trans-stereo-configuration. Thus, the eventualobtention of the more desired 13fl-C/D-transconfiguration in theultimate steroidal products is rendered more facile by thestereoselective reactions provided by this invention.

The final reaction of applicants general process for the compounds ofthis invention is the conversion of the monoene of Formula Ib to theperhydro compound of Formula Ic by reaction of the monoene with acompound having the formula:

R OH VIII wherein R is as previously defined. That is, the monoene ofFormula Ib is reacted with water, a primary alcohol, or a carboxylicacid. This reaction is catalyzed by mineral or organic acids, forexample, hydrochloric acids, phosphoric acid, sulfuric acid,para-toluenesulfonic acid, and the like. Sulfuric acid is the preferredacid catalyst, and water the preferred reactant. Although not necessary,it is desirable to conduct this reaction in the presence of an addedsolvent, particularly in the event the compound of Formula VIII iswater. In this case, it is desirable to employ a solvent which is bothmiscible with water and a solvent for the monoene of Formula Ib.Solvents of this nature include acetone, tert.-butanol, dioxane, and thelike. The reaction temperature is not critical, and ambient temperatureis normally employed, although higher and lower temperatures could beemployed if desired.

As with the compounds of Formulae 121-1 and Ib-l, the compounds ofgeneral Formula Ic wherein Z is carbonyl:

14 wherein Y, R R R R and m are as previously definfd; are readilyconverted to their corresponding alco- YCHQM AM Rn n Ic-2 wherein Y, R RR R R and m are as previously defined; or the fi-hydroxy-a-hydrooarbylcompounds:

wherein Y, R R R R R and m are as previously defined; by the previouslydescribed methods.

In a modification of the general technique outlined above, one cansimultaneously effect the hydrogenation and hydration steps, forexample, by hydrogenation of a diene of Formula la in aqueous sulfuricacid. When this simultaneous hydrogenation-hydroation reaction iseffected, it is preferred to begin with a diene having a hydroxyl groupin the 7f3-position.

As indicated above, the tricyclic compounds which form part of thepresent invention are useful as intermediates for the preparation ofvarious steroid compounds, particularly 19-nor-steroids of the normalseries, as illustrated by the following reaction scheme.

R1 Z Z std XII

wherein R R R R R Y, Z and m are as above.

In the first step of this reaction scheme, the compound of Formula Ic isoxidized to form bicyclic compound of the Formula X by contact with suchoxidizing agents as chromic acid, potassium dichromate, or potassiumpermanganate. Jones reagent (chromic acid, sulfuric acid and acetone),or a chromic acid-acetic'acid mixture are preferred as oxidizing agents.The nature of Z is unchanged in this reaction, except when Z ishydroxymethylene [-CH(OH)-]. In this instance, unless the hydroxyl groupis protected, as by formation of a lower acyl ester, it is oxidized toform a carbonyl group. A hydroxylated product is readily obtained,however, by hydrolysis of a product ester. The reaction temperature isnot narrowly critical, and temperatures in the range of from C. to about75 C. are suitable, although ambient temperatures are preferred.

In the second step, bicyclic compound (X) is treated with acid or baseto effect cyclization to (XI). In this reaction, it is preferred thatthe water of reaction be removed, as by refluxing the reaction mixturewith an azeotroping agent in the presence of a strong acid andseparating the water from the condensate. Suitable strong acids aresulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like.Alternatively, base catalyzed dehydration can be utilized, for example,by refluxing compound (X) in the presence of methanolic sodiumhydroxide.

The hydrogenation of cyclo-olefin XI is preferably effected with a noblemetal catalyst, e.g., a palladium-charcoal catalyst or a rhodiumcatalyst. Mild conditions are generally employed, e.g., room temperatureand atmospheric pressure are convenient conditions for this reaction.The hydrogenated compound of Formula XIa is converted to the desired19-nor-steroid of Formula XII by heating it, preferably at reflux, withdilute aqueous acid, preferably a mineral acid such as hydrochloric acidin a lower alkanol solvent medium, preferably methanol.

Compounds of Formula XI wherein Z is carbonyl can be converted intocorresponding pregnane compounds i.e., compounds in which Z is of theformula by known procedures. Thus, for example, 19-nor-14/3-androst-4-ene-3,17-dione can be converted into 19-nor-14B,17a-progesterone. These procedures for converting androst-17-onesinto pregnanes are best effected if all carbonyl groups other than thatin the 17-position are initially protected.

As has been pointed out above, the products of this invention areproduced in the form of various optically active antipodes which can becarried through the entire reaction sequence, or which can be resolvedat suitable places during the reaction sequence. For example, at anystage wherein a compound having a secondary hydroxyl group is present,such as hydroxytetrahydropyran (IV), or any of the hydroxy compounds ofFormula I, one can react the secondary alcohol with a dicarboxylic acidto form a half-ester. Suitable dicarboxylic acids include lower alkyldicarboxylic acids such as oxalic acid, malonic acid, succinic acid,glutamic acid, adipic acid, or aromatic carboxylic acids such asphthalic acid. The resulting halfester is then reacted with an opticallyactive base, such as brucine, ephedrine, or quinine, to produce adiastereomeric salt. The salts, after separation, are then readilyreconverted to optically active alcohols. As an alternative, thesecondary alcohols can be reacted with an optically active acid, forexample, camphorsulfonic acid. The resulting diastereomeric esters arethen separated and reconverted to the alcohols.

It is preferred that the resolution be effected at some stage in thesynthesis of alken-3-one, as by the abovementioned resolution ofhydroxytetrahydropyran (IV). In a more preferred technique opticallyactive S-alkyl-S- valerolactone is obtained from 5-alkyl-5-oxopentanoicacid via known microbiological processes. The S-form of this lactone isthe preferred form for use in accordance with this invention. In a thirdmethod, the racemic lactone can be hydrolyzed to the correspondinghydroxy acid, which is then resolved by treatment with an opticallyactive base in the manner described above. Still other methods will beapparent to those skilled in the art. Resolution at such early stages inthe overall process described herein is highly preferred because of theimproved efficiency in the production of steroids having a desiredstereo-configuration. Because the stereo-configuration is retainedthroughout the synthesis of alken-3-one (II), and further because thecondensation of alken-3-one or variant (II, IIa or IIb) withcycloalkanedione (III) is stereospecific, one, by proper selection ofstereo-isomers at these early stages, can ensure that substantially allof the tricyclic compounds of this invention and the steroids derivedtherefrom have a selected stereo-configuration. Thus, by this technique,the production of compounds of the undesired configuration is minimizedor prevented entirely, with an attendant increase in the efiiciency ofthe production of compounds of the desired configuration.

In the claims, all compounds shall be construed to include,independently, the racemic form of the compound and independently, eachenantiomeric form, i.e., the d and l configurations unless specificallyindicated otherwise.

The following examples are illustrative. All temperatures are in degreecentigrade and all products having centers of asymmetry are racemicunless specifically indicated otherwise.

EXAMPLE 1 (:L )-9,9-ethylenedioxy-S-hydroxy-decanoic acid lactone 25 g.of the hemiacetal, (i)6-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]tetrahydropyran-Z-ol was dissolved in a mixture of dimethylformamide(DMF) acetic acidwater-sodium acetate (anhydrous) (250 ml.; ml. H O/120ml. DMF/40 ml. AcOH/24 g. NaOAc). Bromine (7 ml.) was then added to thecold (5-10") solution over 2-5 min. and the mixture was then stirred fora further 45 min. at room temperature. Aqueous sodium bisulphitesolution and brine were then added and the organic products wereisolated with benzene (5X ml.). The benzene extracts were washed withsaturated brine solution (5X 50 ml.) and then taken to dryness in vacuo.The crude lactone, (i)-9,9-ethylenedioxy-5-hydroxy-decanoic acid lactoneyielded pure material on distillation, B.P. 138-140/ .02 mm.

In another experiment the hemiacetal, *-)-6-[3-(2- methyl 1,3dioxolan-2-yl)propyl] tetrahydropyran-Z-ol gave the lactone,(i)-9,9-ethylenedioxy-S-hydroxy-decanoic acid lactone, B.P. 141-145/.3mm.

The starting material may be prepared as follows:

A solution of 2,2-ethylenedioxy-5-chloropentane in tetrahydrofuran (THF)(50 ml.; 164 g. in 1600 ml. THF) was added to magnesium (38 g.)activated with a crystal of iodine. This mixture was stirred and heatedat reflux until the reaction commenced. The rest of the chloroketalsolution was then added over approximately 1 hr. to sustain gentlereflux. After complete addition, the mixture was stirred at roomtemperature for a further 2 hrs.

A. solution of freshly distilled glutaraldehyde (110 g.) in THF (1000ml.) cooled to 40 was treated with the above Grignard reagent (asrapidly as possible) and then stirred 30 min. at -30 and a further 1 hr.at 0. Aqueous ammonia chloride solution (300 ml.; 25 percent) was thenadded and the products were isolated with ether. Removal of the solventsin vacuo gave the product as a mobile liquid (185 g.). This material wasstirred at 50 with aqueous sodium sulfite solution (1500 ml.; 20percent) and the pH was adjusted first to pH 6.5 with acetic acid andthen pH 7.5 with sodium hydroxide solution (20 percent). The aqueousphase after stirring for 1 hr. at 50 was extracted with ether and thentreated with caustic soda solution (20 percent) to pH 12. Extractionwith benzene then furnished the hemiacetal -)-6-[3-(2- methyl 1,3dioxolan Z-yl)propyl]tetrahydropyran-Z-ol (118 g.) as a mobile, paleyellow liquid. A sample was distilled (molecular still) to give acolorless product, B.P. 132/.1 mm.

1 7 EXAMPLE 2 (i)-9-oxo-5-hydroxydecanoic acid lactone 52.4 g. of theketal lactone, (i)-9,9-ethylenedioxy-- hydroxy-decanoic acid lactonedissolved in acetone (150 ml.) was treated with water (75 ml.), diluteaqueous sulphuric acid (2 N; 45 ml.) and left to stand at roomtemperature for 16 hr. Addition of brine and extraction with benzenegave the crude lactone, (:)-9-oxo-5-hydroxydecanoic acid lactone whichon distillation, yielded pure material 98 percent pure by VPC, B.P.134/.05 mm.

EXAMPLE 3 i )-9,9=phenylenedioxy-S-hydroxy-decanoic acid lactone 15 g.of a solution of the ketolactone (:)-9-oxo-5-hydroxydecanoic acidlactone in benzene (300 ml.) was treated with 20 g. catechol and 0.6 g.p-toluenesulphonic acid (PTS). The mixture was heated at reflux undernitrogen in conjunction with a soxhlet extraction apparatus equippedwith a thimble filled with calcium hydride. After 18 hr. at reflux themixture was cooled and chromatographed directly on silica gel (.2.5 mm.mesh; 650 g.). Elution with 5%, and ethyl acetate-benzene mixturesyielded the ketal ester.

Distillation of the above material gave catechol and the desiredlactone, (i)-9,9 phenylenedioxy-5-hydroxy-decanoic acid lactone, B.P.152170/.2 mm. (This was a short path distillation and the majority ofthe material had B.P. 157-162). A sample of this material wasredistilled (Kugel Rhor) and gave material, B.P. 140-54/ .02 mm.

EXAMPLE 4 (i) 6 (4,4 phenylenedioxypentyl) 2 (2diethylaminoethyl)-tetrahydropyran-2-ol 1.6 g. of the ketal lactone,(i)-9,9-phenylenedioxy-S-hydroxy-decanoic acid lactone intetrahydrofuran (THF; 15 ml.) was cooled to 45 and treated over 5 min.with a solution of vinyl magnesium chloride in THF (4.6 ml.; 2mol/liter). After stirring a further 25 min. at 45", methanol (5 ml.)was added followed by an aqueous ammonium chloride solution (15 percent;ml.) The products were extracted into ether and the ether extracts thentreated with diethylamine (5 ml.) was dried over magnesium sulphate.Removal of the solvents in vacuo gave the crude Mannich base which wasseparated from neutral material with dilute aqueous acid (1 N H 80 4X 15ml.). The aqueous extracts were made basic with caustic potash solutionand the products isolated with ether. Removal of the solvents in vacuogave the Mannich base, i- )-6- (4,4-phenylenedioxypentyl) -2-(2-diethylaminoethyl)-tetrahydropyran-2-ol as a mobile liquid.

This material showed one spot on TLC analysis on development with abenzene/triethylamine (9:1) system.

EXAMPLE 5 (i) 3 (4,4 phenylenedioxypentyl)-6a,;3-methyl-1,2,3,

5,6,6a hexahydrocyclopenta [f] [1]benzoyyran-7( 8H)- one 10.6 g. of theMannich base, -)-6-(4,4-phenylenedioxypentyl) 2 (2diethylaminoethyl)-tetrahydropyran- 2-ol in toluene (80 ml.) was addedrapidly to a refluxing solution of 2-methylcyclopentan-1,3-dione (4.7g.) in toluene (50 ml.), acetic acid (23.2 ml.) and pyridine (7.2 ml.)

under nitrogen. After heating at reflux for a total of 4 hr.

(reaction followed by TLC) the mixture was cooled,

diluted with toluene (100 ml.) and extracted with water (4X 50 ml.),saturated aqueous sodium bicarbonate solution (1X 50 ml.), brine (1X 50ml.) and dried over M gSO Removal of the solvents in vacuo yielded thecrude crystalline dienolether, (i-)-3-(4,4-phenylenedioxypentyl) 6a,;8methyl 1,2,3,5,6,6a-hexahydrocyclopenta [f] [1]benzopyran-7(8H)-one,M.P. 115120. A sample of this material was recrystallized frombenzene-hexane mixture to give pure material, M.P. 126129.

18 EXAMPLE 6 (i) 3 (4,4 phenylenedioxypentyl)-6a,B-methyl-1,2,3,

5,6,6a,7,8 -,octahydrocyclopenta[f] [1]benzopyran 7fi- 01 10.7 g. of thecrude dienolether, (:)-3-(4,4-phenylenedioxypentyl) 6a,;8methyl-l,2,3,5,6,6a-hexahydrocyclopenta[f] [1]benzopyran-7(8H)-onedissolved in THF/ ether ml.; 1:1) was added to a slurry of lithiumaluminum hydride (4 g.) in a THF/ether mixture (400 ml.; 1:1) cooled inan ice-salt bath (temp. held at -3). After complete addition the mixturewas stirred for a further 10 min. at 5 and 1% hrs. at room temperature(followed by TLC). Wet ether (100 ml.) was then added followed by asaturated aqueous solution of sodium sulphate (25 ml.). The coagulatedsalts were then filtered off, washed with THF and the filtrate was driedover MgSO. Removal of the solvents in vacuo gave the crude alcohol, i-)-3- (4,4-pheny1enedioxypentyl) -6a,/3-methyl- 1,2,3,5,6,6a,7,8octahydrocyclopenta[f] [1]benzopyran- 7 B-ol.

EXAMPLE 7 (i) 3 (4,4 phenylenedioxypentyl) 6a,fi-methyl-1,2,

3,5,6,6a,7,8,9,9a decahydrocyclopenta[f] [1]benzopyran-7,8-ol

11.2 g. of the crude dienolether alcohol, (i)-3-(4,'4-phenylenedioxypentyl) 6a,,8 methyl l,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7fl-ol (this still contains somesolvent) was dissolved in toluene (100 ml.) treated with 2 g. of a 5%Pd/C catalyst and hydrogenated at room temperature and pressure. After 5/2 hrs. the uptake of hydrogen stopped (635 ml.; theory 700 ml. at roomtemperature and pressure for 10.7 g.) and the solids were filtered OEand Washed with toluene. Removal of the solvents in vacuo gave the enolether, (:)-3-(4,4- phenylenedioxypentyl) 6a,fi methyl l,2,3,5,'6,6a,7,8,9,9a-decahydrocyclopenta[f] [11benzopyran-7B-ol, as an oil.

EXAMPLE 8 (i)-4-(3-oxo-7,7-phenylenedioxyoctyl)-1a,/3-methylperhydroindan-1,5-dione10.76 g. of the crude enol ether,(i)-3-(4,4-phenylenedioxypentyl)-6a,fi-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][l]benzopyran-7,B-ol dissolved in acetone (210 ml.) was treated withaqueous sulphuric acid solution (50 ml.; .5 N) and left at roomtemperature for 2 hrs. (followed by TLC). Dilution with ether (500 ml.)and washing with brine (5 X 100 ml.) and saturated aqueous sodiumbicarbonate solution (1 50 ml.) [all aqueous extracts were backwashedwith ether (1x100 1.)] gave the hemiketal,(i-)-3-(4,4-phenylenedioxypentyl)-6a,8- methyl4-hydroxyperhydrocyclopenta [f] [l]benzopyran 75-01 as a glass.

This material was virtually pure by TLC and showed no enol ether band inthe LR. The strong hydroxyl bands at 3450 and 3757 cm. and thecharacteristic catecholketal bands were most pronounced. 10.37 g. ofthis crude hydration product, was dissolved in acetone (200 ml.)

cooled in an ice bath and treated at 0-5 with fresh.

Jones chromic acid mixture (20 ml.) over 10 min. After stirring afurther 1 /2 hrs. at room temperature, aqueous sodium bisulphitesolution (100 ml.; 10%) and brine (100 ml.) were added and the organicmaterials were isolated with benzene (4X 200 ml.). The benzene extractwas washed with brine and aqueous sodium carbonate solution (10%) togive the neutral triketone, (i) 4 (30x0-7,7-phenylenedioxyoctyl)-la,B-methylperhydroindan-1,5-dione as apale yellow liquid. This material showed one major spot on TLC and hadbands in the LR. spectrum (film) at 1730 cm." (cyclopentanone, 1705 cm.-(saturated carbonyl) and 1480, 1240 and 730 cm." (catechol ketal).

19 EXAMPLE 9 (i) 6 (3,3 phenylenedioxybutyl) 3a,;3 methyl- 4,5,8,9,9a,9bhexahydro 1H benz[e]indene 3,7 (2H,8H)-dione 8.6 g. of a solution of thecrude triketone, )-4-(3- oxo 7,7phenylenedioxyoctyl)-1a,fl-methyl-perhydroindan-1,S-dione in methanol(250 ml.) containing 1 g. of potassium hydroxide was heated at reflux,under nitrogen, for 1 hr. (followed by I.R.). Benzene (500 ml.) wasadded and the mixture was extracted with dilute aqueous sulphuric acid(3X 50 ml. .5 N), saturated sodium bicar bonate solution (1 x 100 ml.),brine and then dried over MgSO (note: all aqueous extracts werebackwashed with benzene). Removal of the solvents in vacuo furnished thecrude tricyclic material, (i)-6-(3,3-phenylenedioxybutyl) 3a,f3 methyl4,5,8,9,9a,9b-hexahydro-lH-benz [e]indene-3,7(2H,8H)-dione as asemi-solid. This material was digested with ethanol (50 ml.) to give thecrystalline material, M.P. 166-170".

A sample of this material was recrystallized from ethanol to yield purecolorless crystals, M.P. 173175.

EXAMPLE (i )-19-nor-androst-4-ene-3,17-dione 4.01 g. of crude(i)-6-(3,3-phenylenedioxybutyl)-3a, 13 methyl4,5,8,9,9a,9b-hexahydro-1H-benz[e]indene- 3,7-(2H,8H)dione was dissolvedin THF (45 ml.) containing triethylamine (.8 ml.) and 400 mg. of a 5percent Pd/C catalyst and hydrogenated at room temperature and pressure.After 6 hrs., the uptake of hydrogen ceased (280 ml. consumed; theory285 mL/RTP). The solids were filtered off, washed with THF and thefiltrate was taken to dryness in vacuo. The crude hydrogenation prodnet(i- )-6-(3,3-phenylenedioxybutyl)-3a,B-methyl-4,5,5a, 6,8,9,9a,9boctahydro 1H-benz[e]indene-3,7-(2H,8H)- dione (some solvent residue)showed bands in the LR. spectrum (film) at 1705 cm.- (cyclohexanone),1735 cm.- (cyclopentanone) and 1480, 1240 and 740 cm.- (catechol ketal)and was virtually one spot material on TLC. 4.3 g. of this crudehydrogenation material was dissolved in methanol (70 ml.) and 35 ml. of4 N HCl and the solution was heated at reflux for 6 hrs. (followed byTLC and LR). The mixture was cooled, treated with benzene (200 ml.) andextracted with aqueous caustic soda solution (1 N; 3x 100 ml.) and brine(2x 50 ml.). (All aqueous extracts were backwashed with benzene.)Removal of the solvents in vacuo gave crude19-norandr0st-4-en-3,17-dione which on crystallization fromdichloromethane/isopropyl ether mixture yielded pure (i) 19nor-androst-4-ene-3,17-dione, M.P. 155-157, identical in all respectswith authentic (i)-19-nor androst 4 ene 3,17 dione, M.P. Max. M.P. TLC,LR, and U.V.

EXAMPLE 11 (:)-3-(4,4-phenylenedioxypentyl) 621,5 ethy1-1,2,3,5,6,6a-hexahydrocyclopenta f] [l] benzopyran-7 8H -one (i) 2 (2diethylaminoethyl)-6-(4,4-phenylenedioxypentyl)tetrahydropyran-Z-ol (3.8g.) in toluene ml.) was added to a refluxing solution ofZ-ethylcyclopentan-l,3-dione (2 g.) in toluene (40 ml.) and acetic acid(20 ml.) and heated at reflux for 1 hour.

Isolation of the organic materials with toluene gave pure)-3-(4,4-phenylenedioxypentyl)-6a,,B-ethyl-1,2,3, 5,6,6ahexahydrocyclopenta[f][l]benzopyran 7(8H)- one (2.95 g.) afterchromatography on alumina. U.V. (EtOH) A 252 mu. (e 16,000) Calcd. for CH O (percent): C, 76.11; H, 7.67. Found (percent): C, 75.68; H, 7.83.

EXAMPLE 12 (i )-6-(3,3-phenylenedioxybutyl)-3a,B-ethyl-4,5,8,9,9a,9b-hexahydro-lH-benz[e]inden-3,7-(2H,3aH)-dione Crude (i) 3 (4,4phenylenedioxypentyl) 6a,;3- ethyl 1,2,3,5,6,6a hexahydrocyclopenta[f][1]benzo- 20 pyran-7(8H)-one (47 g.) dissolved in tetrahydrofuran (200ml.) was added to a cold (10) slurry of lithium aluminum hydride (6 g.)in tetrahydrofuran (200 ml.)

After stirring for 2 hours at room temperature, saturated aqueous sodiumsulfate solution was added (40 ml.) and the solids were filtered off.

Removal of the solvents in vacuo gave racemic 3- (4,4-phenylenedioxypentyl) 6a,]3 ethyl 1,2,3,5,6,6a,7,8-octahydrocyclopenta[f] [1]benzopyran 7B 01 as an oil (51 g.). I.R.(film) 3400 (OH); 1640 (dienol ether); 1450, 1240 and 730 cm.- catecholketal.

The above crude material was dissolved in toluene, treated with Pd/C(5%; 5 g.) and hydrogenated at room temperature and pressure until thehydrogen uptake stopped (approximately 30 hours).

The solids were filtered off and the solvents removed in vacuo to yieldcrude (:)-trans 3 (4,4-phenylenedioxypentyl) 6a,]?! ethyl1,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta[f] [1] benzopyran 7,3 01 as anoil (48 g.). LR. (CHCl 3425 and 3580 (OH); 1480 cm? (catechol ketal).

The above material was dissolved in acetone (500 ml.) treated withdilute aqueous sulfuric acid (0.5 N; 50 ml.) and left to stand at roomtemperature for 2 hours. The solution was then cooled to 5 and treatedover 30 minutes with fresh Jones chromic acid reagent (125 ml.). Themixture was then stirred for a further 2 hours at room temperature andthen quenched with aqueous sodium bisulfite solution (20%; 50 ml.).

Isolation of the organic materials with benzene and extraction withaqueous sodium carbonate solution gave racemic trans 4 (3 oxo 7,7phenylenedioxyoctyl)- 1a,? ethyl-perhydroindane 1,5 dione (34.4 g.)after removal of the organic solvents in vacuo. LR. (film) 1735(cyclopentanone); 1708 (cyclohexanone and straight chain ketone); 1480;1275 and 740 cm.- (catechol ketal).

The crude bicyclic material (34.4 g.) was dissolved in methanol (110ml.) and added to a reflux solution of potassium hydroxide (3.5 g.) inmethanol (200 ml.).

After 1 hour at reflux the organic materials were isolated with benzeneand chromatography on silica gel (800 g.) gave racemic 6 (3,3phenylenedioxybutyl) 3a,,8- ethyl 4,5,8,9,9a,9b hexahydro 1Hbenz[e]inden-3,7- (2H,3aH) dione (20 g.) as an oil. LR. (CHCl 1735(cyclopentanone); 1663 and 1600 (cyclohexanone); 1480 cm.- (catecholketal).

EXAMPLE 13 i)-13fl-ethylgon-4-en-3,17-dione Racemic 6 (3,3phenylenedioxybutyl) 3a,,B ethyl- 4,5,8,9,9a,9b hexahydro 1Hbenz[e]inden 3,7 (2H, 3aH)-dione (20 g.) was dissolved in ethanol (250ml.) containing triethylamine (2 ml.) and Pd/C (5%; 4 g.) andhydrogenated at room temperature and pressure until the uptake ofhydrogen stopped to yield 6 (3,3 phenylenedioxy) 3a,B ethyl4,5,5a,6,8,9,9a,9b octahydro- 1H-benz[e]indene-3,7-(2H,8H)-dione insolution.

The solids were filtered off and dilute aqueous hydrochloric acid (4 N;200 ml.) Was added and the mixture was heated at reflux for 5 hours.

The organic materials were isolated with benzene and the benzene extractwas then washed free of catechol with dilute aqueous caustic sodasolution.

Removal of the solvents in vacuo yielded a semisolid which oncrystallization from dichloromethane-isopropyl ether mixture yieldedpure racemic l3fl-ethylgon-4-en- 3,17-di0ne (6.3 g.), M.P. 159-161.

EXAMPLE 14 2R,6S 2[2 (R-a-phenethylamino)ethy1]-6-(4,4phenylenedioxypentyl)tetrahydropyran 2 01 and 2S,6R-

2[2 (R-u-phenethylamino)ethyl] 6(4,4-phenylenedioxypentyl)tetrahydropyran-Z-ol (i) 9,9 phenylenedioxy 5hydroxy decanoic acid lactone 11.1 g.) dissolved in tetrahydrofuran 21ml.) at 50 was treated with vinylmagnesium chloride solution (39 ml.; 2molar in T.H.F.) over 3 minutes. The mixture was then stirred at 45 for25 minutes, quenched with methanol (10 ml.) and ammonium chloridesolution (15%; 100 ml.) and extracted with ether.

Removal of the solvents in vacuo gave the crude vinyl ketone as an oil.This material was dissolved in benzene (20 ml.) and treated with asolution of (Rye-phenethylamine (3.9 g.) in benzene (20 ml.) and left atroom temperature for 3 hours.

The solvents were removed in vacuo and the residue extracted withhexane. This hexane extract was filtered through alumina (50 g.) to givethe mixture of diastereomeric bases (11 g.) as a liquid.

This material was dissolved in hexane and left to crystallize.Recrystallization yielded the pure 2S,6R,2-[2-(R or.phenethylamino)ethyl] 6 (4,4 phenylenedioxypentyl)-tetrahydropyran-2-ol, M.P. 72-76; [a ]=+37 (c.=5, benzene).

The mother liquors from the first crystallization were taken to drynessand dissolved in acetone (25 ml.). This solution was added to oxalicacid (2 g.) in acetone (30 ml.) and left to crystallize.

Recrystallization of the solids from acetone yielded pure 2R,6S,2 [2 (Ra phenethylamino)ethyl] 6- (4,4-phenylenedioxypentyl)tetrahydropyran-Z-ol oxalate, M.P. 80; [Ot ]=+21 (c.=1.248, methanol).

EXAMPLE l5 3S,6aS,3 (4,4 phenylenedioxypentyl) 6a,;3 methyl-1,2,3,5,6,6a hexahydrocyclopenta [f] [1]benzopyran- 7(8H)-one 2S,6R 2[2(R a phenethylamino)ethyl]-6-(4,4- phenylenedioxypentyl)tetrahydropyran-Z-ol (1.25 g.) in toluene (45 ml.) and aqueous aceticacid (18 ml.; 95%) was treated with pyridine (9 ml.) and 2methylcyclopentane-l,3-dione (0.5 g.) and heated at 110 for 7 hours.After this time the water was taken 01f with a Dean- Stark separator(-45 minutes) and the mixture cooled.

Isolation of the materials with benzene and chromatography on aluminayielded the dienol ether.

Crystallization from hexane gave optically pure 3S, 6aS,3 (4,4phenylenedioxypentyl) 6a,B methyl 1,2, 3,5 ,6,6a hexahydrcyclopenta[f][1]benzopyran-7(8H)- one, M.P. 109-1l2, [a ]=--121 (c.=1.0, CHCl EXAMPLE16 )-l9-norandrost-4-en-3,17-dione 3R,6aS,3 (4,4 phenylenedioxypentyl)6a,;3 methyl 1,2,3,5,6,6a hexahydrocyclopenta[f] [l]benzopyran-7(8H)-one was converted in good yield into the abovecaptioned producthaving a melting point of 172 using the procedure of Examples 6, 7, 8, 9and 10.

EXAMPLE 17 (i -6- (4,4-phenylenedioxypentyl -tetrahydropyran-2-olFreshly distilled glutaraldehyde (100 g.) dissolved in dry THF (700 ml.)was cooled to --65 and treated rapidly with the cold (-20) Grignardreagent over -30 min. (the temperature was held at -60+50 C. with a DryIce acetone bath). The mixture was then allowed to warm up to roomtemperature (-1 hr.) and then stirred a further 90 min. at roomtemperature (Note: sometimes on warming to room temperature an exothermsets in and cooling is required). The reaction mixture can be stored16-24 hrs. at or worked up after 90 min. at room temperature.

To work up, the reaction mixture was cooled to 5 and treated with anaqueous solution of ammonium chloride (150 ml.; 25 percent). The solidswere filtered off, washed well with more THF and the THF was removed invacuo 22 to yield the crude hemi-acetal (i) 6 (4,4-phenylenedioxypentyl)tetrahydropyran 2 01 (270 g.). This material assayed for -75 percentpurity by chromatography on silica gel.

The starting material may be prepared as follows:

(A) Preparation of the Grignard reagent: A total of ml. of a solution of2,2 phenylenedioxy 5 chloropentane in dry tetrahydrofuran obtained byadding 213 g. of the chloroketal to 1.4 l. of THF istilled from calciumhydride was added to 28 g. of magnesium turnings activated with iodineunder nitrogen.

The mixture was then heated to 36-38 for -5 min. and then treated withdibromoethane (.5 ml.). In general, the reaction became mildlyexothermic at this point and had to be cooled to maintain thetemperature range of 36-38 C. After stirring 15-20 min. more, the restof the chloroketal solution was added over -1 hr. Again cooling wasrequired. After stirring a further 45-60 min. the exotherm subsided andthe mixture was heated to 36-38 for a further 2 hours after which timevirtually no starting material remains.

The Grignard reagent can be stored under nitrogen at 5 for several days.The progress of the reaction was followed by vapor phase chromatography.Thus, an aliquot .5 ml.) of the reaction mixture was added to aqueousammonium chloride solution (2 ml.; 15 percent) and ether (.5 ml.). Theorganic extract was then analyzed at C. on an 8' x A" column with 3percent SE 30 silicone on chom. w. (80-100) AW-DAKS.

(B) Production of dry glutaraldehyde: Aqueous glutaraldehyde solution (11.: 50 percent Union Carbide) was treated with benzene (2 l.) cooled to5 and dried with magnesium sulfate (700 g.) for 15 min. The solution wasthen heated at reflux for 1 hr. in conjunction with a Dean and Starkwater separator. The solvents were then removed in vacuo (50 at 10 mm.)and the residue distilled to give a center cut (315 g.) of dryglutaraldehyde, B.P. 80-81/-10 mm.

EXAMPLE 18 (i-)-9,9-phenylenedioxy-S-hydroxy-decanoic acid lactone (a) Asolution of sodium hydroxide (91 g.) in water (225 ml.) was added tosilver nitrate g.) dissolved in water (650 ml.) at room temperature andthen the mixture was heated to 55-60. Methanol (1300 ml.) was then addedand the temperature fell to 45 A solution of (i) 6 (4,4phenylenedioxypentyl) tetrahydropyran 2 01 (107.7 g. crude) in methanol(150 ml.) was then added over 10 min. The temperature rose to 53 andafter the initial exotherm the mixture was heated, with stirring, undernitrogen for a further 1 hr. The solids were filtered off and washedwell with a methanol-water mixture (1:1; 3 200 ml.). The filtrate wasthen extracted with toluene (500 ml.) acidified to pH 1 with aqueoussulfuric acid (6 N) and extracted with dichloromethane (4X 500 ml.).Removal of the solvents in vacuo yielded a mixture of the lactone andhydroxy acid (83 g.). This material was dissolved in benzene (500 ml.)and treated with p-toluenesulfonic acid (2 g.) in more benzene (100ml.). After standing for 1 hr. at room temperature the mixture waswashed with aqueous sodium bicarbonate solution and the organic solventswere removed in vacuo to yield virtually pure lactone(i)-9,9-phenylenedioxy 5 hydroxy decanoic acid lactone (76 g.) (asestimated by TLC and I.R.).

(b) The hemiacetal (i) 6 (4,4 phenylenedioxypentyl) tetrahydro pyran 201 (1.77 g.) in ethyl acetate (100 ml.) containing platinum black (922mg.) was stirred at room temperature under an atmosphere of oxygen for48 hrs. The solids were filtered off and the product (i) 9,9phenylenedioxy 5-hydroxy-decanoic acid lactone was isolated bydistillation 1.5 g.).

(c) The crude hemiacetal (i) 6 (4,4 phenylenedioxypentyl)tetrahydropyran2 01 (233 g.) dissolved in toluene (1.2 1.) was added to a solution ofsodium dichromate bishydrate (315 g.) in acetic acid 1.2 1.). Thereaction mixture was held at 35 with cooling until no longer exothermic(-2 hrs.), and then stirred -16 hrs. at room temperature. Water (2.5 l.)was added and the materials were isolated with toluene (4X 500 ml.). Thecombined toluene extracts were washed with brine and distilled to givethe lactone (i)9,9-phenylenedioxy- 5-hydroxydecanoic acid lactone (125g.) of moderate purity (-80 percent). A purer product was obtained whenthe toluene layer was washed first with aqueous sodium bicarbonatesolution (44-46 percent yield v.p.c. pure).

(d) The crude hemiacetal (i) '6 (4,4phenylenedioxypentyl)-tetrahydropyran-2-ol (78 g.) in DMF (400 ml.) wasadded to a solution of bromine (30.5 ml.) in a buffer mixture (640 ml.)(420 ml. H O/480 DMF/160 ml. AcOH/ 160 g. NaOAc-2H O) at -5 C.

After stirring 1 hr. at room temperature, aqueous sodium bisulfite wasadded (250 ml.; 15 percent) and the organic materials were isolated withbenzene. Removal of the solvents gave a brown colored oil which wadissolved in methanol (500 ml.) and treated with potassium hydroxide (30g.) dissolved in water (.300 ml.). After 30 min. at room temperature,water (500 ml.) was added and the mixture was extracted with ether. Theaqueous phase was acidified and extracted with methylene chloride.Removal of the solvents in vacuo and distillation of the residue (oiljacketed flask at .3 mm.) gave the lactone(1-)-9,9-phenylenedioxy-S-hydroxy-decanoic acid lactone (29-33 g.). Thismaterial was contaminated by some aromatic-ring brominated material.

EXAMPLE 19 2S,6R-2- 2- (S-a-phenethylamino ethyl] -6- (4,4-pheny1-enedioxypentyl) -tetrahydropyran-2-ol oxalate The lactone (i) 9,9phenylenedioxy 5 hydroxydecanoic acid lactone (118 g.) dissolved in THF(1 l.) was cooled to -70 C. under nitrogen. A solution of vinylmagnesium chloride (315 ml.; 2.28 molar) in THF was added over 6 min.(temp. held between -50 and 70) and the mixture was then stirred afurther 14 min. at -50. After this time the temperature was lowered to-65 and methanol (50 ml.) was added (3 min.) followed by aqueousammonium chloride solution (500 ml.; percent). (The temperature rose to-5.)

The products were then isolated with ether (5X 500 ml.) and dried withMgSO. The solids were filtered off and the filtrate was concentrated to-200 ml. in vacuo at 40-45". The concentrate was treated with benzene(250 ml.) and a solution of (S)-a-phenethylamine (51 g.) in benzene (150ml.) and kept at room temperature overnight (3-4 hrs. will suflice;slight cooling is initially required). The solvents were taken todryness and the residue (193 g.) was extracted with boiling hexane (1 x500 ml. and 2X 250 ml.) and the combined hexane extracts were againtaken to dryness in vacuo. The residue (157.2 g.) was dissolved inacetone (400 ml.) and added to a solution of oxalic acid (49 g.) inacetone (400 ml.). After standing 8 hrs. at room temperature and 8 hrs.at -5, the solids were filtered off, washed with acetone (2X 100 ml.)and dried over P 0 at .5 mm. This solid (84.2 g.) had M.P. 78-82", [ab-21 (c.=6.45, methanol) and was recrystallized from methyl ethyl ketone1.1. 1.) (some insoluble solids were filtered ofl) and gave pure 2S,6R 2[Z-(S-a-phenethylamino)ethyl]-6-(4,4-phenylenedioxypentyl)-tetrahydropyran-2-oloxalate (51.2 g.), M.P. 81-83 a 23.3 (c.=3.95, methanol).

Analysis.-Calcd. for C H NO (CO H) (percent): C, 65.23; H, 7.23; N,2.72. Found (percent): C, 64.91; H, 7.09; N, 2.49.

All the mother liquors were taken to dryness and the residue waspartitioned between water (800 ml.) and 24 hexane (400 ml.). The aqueousphase was re-extracted with hexane (400 ml.) and the combined hexaneextracts were then washed with aqueous acetic acid (10 percent).

All the aqueous phases were combined and made basic with sodiumcarbonate solution (130 g. in 400 m1. H O). The organic materials wereextracted into hexane and yielded an oily solid on concentration (75g.). This material was recrystallized three times from hexane to givepure 2R,6S 2 [2-(S-a-phenethylamino)-ethyl]-6-(4,4-phenylenedioxypentyl)-tetrahydropyran-2-ol (40 g.), M.P. 78-80"; [a] 37(c.==3.42; benzene).

Analysis.-Calcd. for C H NO (percent): C, 73.38; H, 8.29; N, 3.29. Found(percent): C, 73.68; H, 8.40; N, 3.47.

All the above mother liquors were taken to dryness and dissolved in amixture of acetone (100 ml.) and dilute aqueous sulfuric acid (1 N; 100ml.) and left to stand at room temperature for 2 hrs. The mixture wasmade basic with aqueous sodium carbonate solution and the products wereisolated with hexane. (This hydration procedure was necessary asextensive dehydro Mannich base was generated in all the manipulations;particularly in the oxalate recrystallization) The crude extract (-19g.) in acetone (50 ml.) was added to oxalic acid (6.5 g.) in moreacetone (50 ml.). Recrystallization of the precipitate (15.8 g., M.P.75- 78) from methyl ethyl ketone gave a further quantity of pure oxalatesalt (12.9 g.) [@11 23.6 (c.=3.19, methanol).

(Note: Both the melting points and the rotations of the oxalate saltsare dependent on the severity of the drying. This is probably due to thepossible formation of solvates).

EXAMPLE 20 2S,6R-2- 2- (R-a-phenethylaminoethyl] -6-(4,4-phenylenedioxypentyl) -tetrahydropyran-2-ol The procedure ofExample 19 was repeated with the enantiomeric amine(R)-a-phenethylamine. Thus, the lactone i)-9,9-phenylenedioxy-S-hydroxy-decanoic acid lactone (54 g. 80-90percent purity) generated a crude base g.) which was processed asfollows.

The crude product was partitioned between methanolwater-hexane-aceticacid (300:3001501350 ml.). The hexane extract was washed withmethanol-water-acetic acid ml.; 1:1:0.2). The combined aqueous phaseswere then extracted with hexane/benzene mixture (400 ml.; 2:1) and thenmade basic with cold aqueous caustic potash (4 N; -250 ml.) (gave bademulsion). Extraction with hexane then gave the purified amine base (58g.) as an amber colored oil. Crystallization from hexane gave pure2S,6R-2-[2-(R-u-phenethylamino)ethyl] 6 (4,4-phenylenedioxypentyl)tetrahydropyran-Z-ol (17.7 g.; after combiningother crops). M.P. 75-77, [a] +37 (c.=1.053; benzene).

Analysis.Calcd. for C H NO (percent): C, 73.38; H, 8.29; N, 3.29. Found(percent): C, 73.63; H, 8.41; N, 3.26.

All the hexane mother liquors were taken to dryness (37 g.), dissolvedin acetone (100 m1.) and added to oxalic acid (14 g.) dissolved inacetone (100 ml.). The solid formed (31 g.) was recrystallized frommethyl ethyl ketone (250 ml.) to give 2R,6S-2-[Z-(R-a-phenethylamimo-ethyl] 6- (4,4-phenylenedioxypentyl -tetrahydropyran-2-ol oxalate (26.6g.), M.P. 81-83 [a] +22.7 (c.=-4; methanol).

Analysis.Calcd. for C H NO (CO H) (percent): C, 65.23; H, 7.23; N, 2,72.Found (percent): C, 65.31; H, 7.31; N, 2.7.

EXAMPLE 21 3S,6aS-3-(4,4-phenylenedioxypentyl)-6a,B-methyl-1,2,3,5,6,6a-hexahydrocyclopenta [f] [1]benzopyran-7 (8H)-one (a) From2S,6R-2-[Z-(R-a-phenethyIamino)ethyl]-6-(4,4-phenylenedioxypentyl)tetrahydropyran 2 01: The

crystalline free base 2S,6R-2-[2-(R-a-phenethylamino)-ethyl]-6-(4,4-phenylenedioxypentyl)-tetrahydropyran-2-ol (15.02 g.) wasdissolved in a mixture of methanol (300 ml.) benzaldehyde (5.42 g.) andsodium bicarbonate (1.07 g.) and heated at reflux, under nitrogen, for11 hrs. The solvents were removed in vacuo and the residue waspartitioned between ether and dilute aqueous hydrochloric acid (2 N).The ether layer was then washed with aqueous sodium bisulfite solution(BX 100 ml.; 20 percent), brine and dried over sodium sulfate. Removalof the solvents in vacuo yielded the methanol adduct 2S-(2- methoxyethyl-6R- 4,4-phenylenedioxypentyl tetrahydropyran-2-ol (12.6 g.) as an oil+8.94 (c.-=1.6328, benzene) having I.R. bands (film) at 3475 (OH): 1712(open ketohydroxy form; 1490, 1240 and 740 cm.- (catechol ketal). Thiscompound presumably comprises the open and closed form tautomers. Thecrude methanol adduct 12.6 g.) was dissolved in a mixture of toluene(300 ml.), acetic acid (150 ml.), water ml. containingZ-methylcyclopentan-1,3-dione (4.47 g.) and heated at reflux for 8 hrs.A Dean and Stark water trap was then attached and the mixture was heatedat reflux for a further 90 min. The mixture was cooled, treated withbenzene (500 ml.) and washed with water, aqueous sodium carbonatesolution and dried over MgS0 Removal of the solvents in vacuo gave anorange colored gum (15.3 g.). Crystallization from isopropyl alcohol(140 ml.) gave the dienol ether 3S,6aS-3(4,4-phenylenedioxypentyl)-6a,/3- methyl 1,2,3,5,6,6ahexahydrocyclopenta[f] [1]benzopyran-7,(8H)one (7.9 g.).Recrystallization gave pale orange needles (7.3 g.), M.P. 112-113", [041122.3 (c.=1.15; chloroform).

Analysis.Calcd. for C H O (percent): C, 75.76; H, 7.42. Found (percent):C, 75.99; H, 7.63.

(1)) From 28, 6R-2-[2-(S-a-phenethylamino)ethyl]-6- (4,4phenylenedioxypentyl) tetrahydropyran-Z-ol oxalate: The oxalate salt (a23.3; 15.45 g.) was dissolved in methanol (360 ml.) containing sodiumbicarbonate (6 g.; anhydrous) and 'benzaldehyde (4.5 ml.) and heatedunder nitrogen at reflux for 16 hr. The methanol'adduct was then workedup as in (a) above to yield the methanol adduct as a pale yellow coloredoil (9.9 g.); I.R. (film) 3450 (OH), 1700 (sat. C:O open hemiketal).1480, 1260, 770 (catechol ketal), 1100 cm. (methoxy). Conversion of thisproduct to the dienol ether followed the procedure of (a) above and gavepure 3S, 6aS,3-(4,4-phenylenedioxypentyl) 6a,? methyl- 1,2,3,5,6,6ahexahydrocyclopenta[f] [1]benzopyran 7, (8H) one (5.5 g.), [111 121(c.=-2; chloroform).

(0) Direct conversion of 2S,6R-2-[2-(R-a-phenethylamino)ethyl] 6 (4,4phenylenedioxypentyl)tetrahydropyran-Z-ol: A total of 850 mg. of2S,6R-2[2-(Ra phenethylamino)ethyl] '6 (4,4 phenylenedioxypentyl)tetrahydropyran-Z-ol was dissolved in a mixture of toluene (30 ml.),aqueous acetic acid (12 ml.; 90 percent) pyridine (6 ml.),2-methylcyclopentan-1,3-dione (330 mg.) and heated at reflux undernitrogen for 16 hr. A Dean and Stark water trap was then attached andthe water was separated for 35 min. Work up as in (a) above andfiltration of the crude product through alumina (50 ml.; grade IIIneutral) gave the dienol ether mixture (575 mg.) as a pale yellow solid.Crystallization from isopropyl alcohol gave3S,6aS-3-(4,4-phenylenedioxypentyl) 6a,;3methyl-l,2,3,5,6,6ahexahydrocyclopenta[f] [1]benzopyran 7,(8)-one asneedles (397 mg.)

[a] 119 (c.=-2; chloroform); recrystallization raised the rotation to[0th, -121.

EXAMPLE 22 C/D-trans-3-(4,4 phenylenedioxypentyl)-6a,B methyl-1,2,3,5,6,6a,-7,8,9,9a decahydrocyclopenta[f] [11benzopyran-75-ol Thedienol ether 3S,6aS-3-(4,4-phenylenedioxypentyl)- 6a,;3-methyl1,2,3,5,6,6a hexahydrocyclopenta[f][1] 26 benzopyran-7,(8H)-one (14 g.)dissolved in THF ml. was added to a slurry of lithium aluminum hydride(5 g.) in THF (100 ml.) at 5 C. After stirring for 2 hr. at roomtemperature wet ether (200 ml.) and saturated aqueous sodium sulfatesolution (30 ml.) was added. After stirring a further 1 hr. at roomtemperature the solids were filtered OE and washed with ether. Afterdrying the combined filtrate over MgSO the solvents were taken todryness in vacuo to yield a glass (15.5 g.). This material was dissolvedin dry THF (100 ml.), treated with 5 percent Pd/C (1.5 g.) andhydrogenated at room temperature and pressure. After one mole ofhydrogen had been consumed (usually 2-8 hr. required), the solids werefiltered off, washed with more THF and the combined filtrates taken todryness in vacuo. This gave a mixture of the above-titled enol ethers(15 g.). The N.M.R. spectrum showed two methyl signals for the C methylindicating -3:l mixture of the C/D trans to the C/ D cis isomers.

EXAMPLE 23 (+)-6-(3,3-phenylenedioxybutyl) 3a,)? methyl-4,5,8,

9,9a,9b-hexahydro-1H-benz[e]indene-3,7 (2H,3aH)- dione The crudeenol-ether mixture C/D trans-3-(4,4-phenylenedioxypentyl) 6a,;3 methyl1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][1]benzopyran 719 01 (15 g.)dissolved in acetone ml.) was treated with aqueous sulfuric acid (.5 N;50 ml.) at room temperature for 2 hrs. (followed by TLC). Brine (500ml.) was added and the products were isolated with ether to give a glasswhich contained a major amount of 3-(4,4-phenylene dioxypentyl) 4hydroxy-6a,j8-methyl-perhydrocyclopenta[f][1]benzopyran-7fi-ol. Thismaterial dissolved in acetone (300 ml.) was cooled to 0-5 and treatedover 20 min. with fresh Jones chromic acid mixture (45 ml.). The mixturewas then stirred an additional 2 /2 hrs. at room temperature. Aqueoussodium bisulfite solution (100 ml.; 10 percent) and brine (250 ml.) wereadded and the products were isolated by extraction with benzene. Thecombined benzene extracts were washed with dilute sodium carbonatesolution (5 percent; 100 ml.) and taken to dryness in vacuo. The crudetriketone 4- (3-oxo-7,7 phenylenedioxyoctyl)lafi-methyl-perhydroindan-l,5-dione (13.3 g.) showed strong bands in theinfrared spectrum (chloroform) at 1735 and 1710 and 1480 (catecholketal) cm. and no hydroxyl band. The crude triketone was dissolved inmethanol (100 ml.) and added to a solution of potassium hydroxide (2 g.)in methanol (50 ml.) under nitrogen. The deep red colored solution wasthen heated at reflux for 90 min., treated with acetic acid (3 ml.) andtaken to dryness. The residue was partitioned between benzene and sodiumcarbonate solution (5 percent) and gave the crude tricyclic material(+)-6-(3,3-phenylenedioxybutyl)-3a,}3- methyl '4,5,8,9,9a,9b hexahydro1H benz[e]indene- 3,7-(2H,3aH)-dione on concentration to dryness (11.1g.). Crystallization from methylene chloride: isopropyl ether mixture(10:30) gave crystalline material (6.43 g.). This material was dissolvedin ethanol (50 ml.) and left at room temperature, twice filtered free ofsolids (-20 min. intervals) and then cooled to 5 and seeded with pureproduct. After 16 hrs. (at 05) the solids were isolated (4.5 g.), M.P.1l8120, [a] +40.34 (c.=-2; chloroform). From the various mother liquorsa further quantity of material (1.06 g.) was obtained, M.P. 116119, [a]+40.39 (c.=-2; chloroform).

A sample of the bulked material was filtered through alumina (neutral,grade III) in benzene and recrystallized from ethanol to yield theanalytical sample of 6-(3,3 phenylenedioxybutyl) 3a,,3methyl-4,5,8,9,9a, 9b hexahydro 1H benz[e]indene-3,7-(2H,3aH)-dione,M.P. 117l19, [a1 4-40.77 (c.=1.7267, chloroform).

Analysis.Calcd. for C H O (percent): C, 75.76; H, 7.42. Found (percent):C, 75.96; H, 7.31.

EXAMPLE 24 )-19-nor-androst-4-ene-3 l7-dione The tricyclic compound(+)-6-(3,3 phenylenedioxybutyl)3a,;8-methyl-4,5,8,9,9a,9b-hexahydro-lH-benz[e] indene 3,7(2H,3aH)-dione (3.8 g.; [a] +40.34) was dissolved in THF (35 ml.)containing triethylamine (0.7 ml.) and percent Pd/ C (0.4 g.) andhydrogenated at room temperature and pressure until one mole equivalentof hydrogen had been consumed. The solids were filtered off and thefiltrate was taken to dryness in vacuo to yield a colorless glass. Thismaterial was dissolved in ethanol (30 ml.), treated with aqueoushydrochloric acid (2 N; 20 m1.) and heated at reflux under nitrogen for4 hr. The solvents were partially removed in vacuo and the residue wasextracted with benzene. The combined benzene extracts were washed withaqueous sodium carbonate solution percent) and sodium hydroxide solution(1 N). Removal of the solvents gave a white solid (2.8 g.), [a1 +125(c.-=2.2, chloroform). Recrystallization from methylenechloride-isopropyl ether mixture gave crystalline material (2.08 g.),M.P. 169-172 (hot stage), 168-170 (Hoover), [a1 +l39.5 (c. =3.03;chloroform). Recrystallization from aqueous methanol gave pure(+)-19-androst-4-ene 3,17-dione (1.86 g.), M.P. 172174 (hot stage) and168-170 (Hoover), 11 +141.9.

EXAMPLE 25 4,4-(2,3-naphthalenedioxy)-1-chloropentane A mixture of2,3-naphthalenediol (13.3 g.) and 5- chloro-Z-pentanone (5 g.) inbenzene (100 ml.) containing p-toluenesulfonic acid (100 mg.) was heatedat reflux under nitrogen in conjunction with a Dean and Stark water trapfor 18 hrs. The cold reaction mixture was treated with benzene (100 ml.)and washed with aqueous sodium carbonate solution (3X 30 ml.; 10percent), brine and dried over magnesium sulfate (=MgSO -anhydrous). Thesolids were filtered off and the filtrate was passed through a column ofalumina (25 ml.; neutral grade III). Removal of the solvents in vacuogave an oil (7.3 g.) which yielded pure 4,4-(2,3-naphthalenedioxy)-1-chloropentane (5.4 g.) on distillation, B.P.139141/0.07 mm.

Analysis.Calcd. for C H O Cl (percent): C, 68.57; H, 5.75; Cl, 13.49.Found (percent): C, 68.41; H, 5.67; Cl, 13.49.

EXAMPLE 26 4,4- (4,5 -dirnethylphenylenedioxy) -1-ch1oropentane Amixture of 4,5-dirnethylcatehol (34.4 g.) and 5- chIoro-Z-pentanone (30g.) in benzene (600 ml.) containing p-toluenesulfonic acid (600 mg.) washeated, under nitrogen, at reflux in conjunction with a Dean and Starkwater trap for 18 hrs. More benzene (300 ml.) was added and the darkcolored mixture was washed with aqueous sodium carbonate solution (3x150 ml.; 10 percent), brine (250 ml.) and dried over MgSO Removal of thebenzene in vacuo gave a dark colored oil which was dissolved in hexaneand filtered through alumina (175 ml.; neutral grade III).

Removal of the solvent and distillation of the pale yellow colored oil(47.4 g.) yielded pure 4,4-(4,5dimethylphenylenedioxy)-l-chloropentaneafter distillation (39.8 g.), B.P. 110-120/0.1 mm.

Analysis.Calcd. for C H O CI (percent): C, 64.86; H, 7.12; CI, 14.73.Found (percent): C, 64.66; H, 7.3; Cl, 14.74.

EXAMPLE 27 (i)-6- [4,4 (2,3-naphtha1enedioxy) pentyl]-tetrahydropyran-Z-ol Magnesium metal (3 g.; powder) was activated withiodine under nitrogen and treated with a solution (70 ml.) of the4,4-(2,3-naphthalenedioxy)-1-chloropentane in tetrahydrofuran (THF) (20g. in 200 ml. THF; distilled from calcium hydride). The mixture washeated to 40 and treated with dibromoethane (-.3 ml.). After the initialexotherm (slight) had subsided the rest of the solution was added. Themixture was then heated at 35-37" for a further 3 /2-4 hrs. withstirring. (The progress of the reaction was followed by quenching analiquot (.5 ml.) with aqueous ammonium chloride solution (2 ml.; 15percent) and ether (.5 ml.) and analyzing the organic phase by V.P.C. at200 C.) Dry redistilled glutaraldehyde (7.6 g.) dissolved in THF (60ml.) was cooled to 60 and treated with the above Grignard reagent (10-15min.) keeping the temperature at 60- 50. The mixture was then warmed toroom temperature over -3 hrs. After this time (TLC indicated completereaction) the mixture was cooled to 5 and treated with aqueous ammoniumchloride solution (45 ml.; saturated). The solids were filtered off,washed well with more THF and the combined filtrate was taken to drynessin vacuo. The crude hemiacetal (:)-6-[4,4- (2,3-naphthalenedoxy)pentyl]tetrahydropyran 2 01 (24.7 g.) was chromatographed on silica gel (750g.; .2-.5 mm. mesh) and yielded pure product (15.6 g.) on elution withbenzene-ethyl acetate mixtures (9:1; 4:1 and 7:3).

Analysis.-Calcd. for C H O (percent): C, 73.14; H, 7.37. Found(percent): C, 72.84; H, 7.67.

IR. showed bands at 3600 (OH), 1470 and 1250 cm.- (naphthalenedioxy).

EXAMPLE 28 i -6- [4,4- (4,5 -dimethylphenylenedioxy pentyl]tetrahydropyran-Z-ol The chloroketal 4,4-(4,S-dimethylphenylenedioxy)-1-chlorpentane (24 g.) in THF (400 ml.) was converted into the Grignardreagent with magnesium (3.65 g.) as in Example 27. The above solutionwas then added to dry redistilled glutaraldehyde (10 g.) in THF ml.) asbefore to yield the crude hemiacetal (i-)-6-[4,4-(4,5-dimethylphenylenedioxy)pentyl] tetrahydropyran 2-01 (32.5 g.) after thesame workup. Chromatography on silica gel (900 g.; .2-.5 mm. mesh)yielded pure material (13.8 g.).

Analysis.-Calcd. for C H O (percent): C, 70.56; H, 8.55. Found(percent): C, 69.73; H, 8.27.

LR. showed bands at 3600 (OH), 1500 and 1260 cm.- (phenylenedioxy).

EXAMPLE 29 (i)-11,1l-(2,3-naphthalenedioxy)-3,7- dihydroxyl-dodecene Thehemiacetal (i)-6-[4,4-(2,3-naphthalenedioxy)pentyl]-tetrahydropyran-2-ol (15 g.) dissolved in THF (60 ml.) wascooled to 5 and treated with a solution of vinyl magnesium chloride(62.4 ml.; 2.2 molar in THF) and stirred at room temperature overnight(23 hrs. are sufficient). Aqueous ammonium chloride solution (30 ml.; 15perent) was added and the solids were filtered off and washed with moreTHF. The combined THF filtrates were taken to dryness in vacuo to yieldthe crude vinyl diol (i)-11,11-(2,3-naphthalenedioxy)-3,7-dihydroxy-1-dodecene (17.2 g.). Chromatography on silica gel (510g.; .2.5 mm. mesh) gave pure product (13.3 g.) on elution withbenzene-ethyl acetate mixtures (7:3; 1:1 and 1:3).

Analysis.Calcd. for C H O (percent): C, 74.13; H, 7.92. Found (percent):C, 73.75; H, 7.80.

29 EXAMPLE 30 (i)-11,1 l- 4,5 -dimethylphenylenedioxy) 3,7-dihydroxy-1-do decene The hemiacetalL)-6-[4,4-(4,5-dimethylphenylenedioxy)pentyl]-tetrahydropyran-2-ol'I(13.7 g.) dissolved in THF (70 ml.) was treated with vinyl magnesiumchloride solution (60.5 ml.; 2.0 molar in THF) as in Example 29. Workupand chromatography on silica gel as in the previous example gave thepure vinyl diol (:)11,11- (4,S-dimethylphenylenedioxy)3,7-dihydroxy-1-dodecene (11.2 g.).

Analysis.Calcd. for C2gH3004' (percent): C, 71.83; H, 9.04. Found(percent): C, 71.79; H, 9.27.

LR. shows bands at 3610 and 3450 (OH), 1500 and 1255 (phenylenedioxy)and 860 cm. (C -CH EXAMPLE 31)-2-(Z-diethylaminoethyl)-4,4-(2,3-naphthalenedioxy)pentyltetrahydropyran-Z-olManganese dioxide (140 g.) was added to benzene (400 ml.) and cooled to-5. Diethylamine (400 ml.) was slowly added followed by a solution ofthe vinyl diol (:)-11,11-(2,3 naphthalenedioxy) 3,7 dihydroxy-ldodecene(14.4 g.) in benzene (100 ml.). The mixture was stirred at roomtemperature for 18 hrs., filtered free of solids and theresidue waswashed well with benzene. Removal of the benzene from the combinedextracts gave a brown colored oil (21.2 g.) This material Was dissolvedin ether (200 ml.) and extracted with cold aqueous hydrochloric acid (1N; 4X 50 ml.). The aqueous phase was made basic with caustic potashsolution (2 N) and the product was isolated with ether. Removal of thesolvents yielded (:L)-2-(2diethylaminoethyl)-4,4-(2,3-naphthalenedioxy)pentyl-tetrahydropyran 2 01(16.2 g.) as an amber colored oil.

I.R. had bands at 3600 (bonded --OH and --NH) 1250 and 1470 cm."(naphthalenedioxy).

EXAMPLE 32 (1*:)-2-(2-diethylarninoethyl)-6-[4,4-dimethylphenylenedioxy)pentyl]-tetraliydropyran-2-ol NH) 1500 and 1260 cmr (phenylenedioxy).

EXAMPLE 33 i )-3- [4,4- 2,5 naphthal'enedioxy pentyl] -6afl-methyl-1,2,3,5,6,6a hexahydro-cyclopenta- [f] [1]-benzopyran- 7 8H -one Amixture of (i)-2-(Z-diethylaminoethyl)-4,4-(2,3-naphthalenedioxy)pentyl-tetrahydropyran-2-ol (1.51 g.), toluene (8 mt),acetic acid (2 ml.) and 2-methylcyclopentan-1,3-diorie (470 mg.) washeated at reflux, under nitrogen for 90 min. Dilution with benzene (50ml.) and extraction with water, aqueous sodium carbonate solution andbrine yielded the dienol ether (1.5 g.) as an orange-yellow colored oil.A sample of this material was filtered through a column of alumina(grade III; neutral; 10:1) in benzene-hexane flzl) mixture. Removal ofthe solvents in vacuo and crystallization of the pale yellow coloredresidue from hexane furnished pure :)3-[4,4- (2,5 naphthalenedioxy)entyH-Gafl-methyl-1,2,3,5,6,6ahexahydro-cyclopenta [f][1]benzopyran7(8H)-one, M.P. ll2-114.

30 Analysis.-Calcd. for C H O (percent): C, 78.11; H, 7.02. Found(percent): C, 78.36; H, 7.30.

EXAMPLE 34 (i)-3-[4,4 (4,5 dimethylphenylenedioxy)pentyl]-6a/3-methyl-1,2,3,5,6,6a hexahydrocyclopenta[f] [1]benzopyran-7 (8H) -one Amixture of (i-)-2-(2-diethylaminoethyl)-6-[4,4-dimethylphenylenedioxy)pentyl]-tetrahydropyran-2-ol (1 1.5 g.), toluene (60 ml.), acetic acid(15.2 ml.) and 2-methylcyclopentane-1,3-dione (3.6- g.) was heated atreflux for 1 hour and then 30 min. more in conjunction with a Dean andStark water trap. Workup as in Example 33 gave the dienol ether as abrown-red colored solid 11.1 g.). A sample of this material afterfiltration through alumina (neutral; grade III) yielded pure (i) 3[4,4-(4,5-dimethylphenylenedioxy)pentyl] -6aB-methyl1,2,3,5,6,6ahexahydrocyclopenta[f] [1]benzopyran 7(8H)-one oncrystallization from hexane, M.P. 125-127.

Analysis.Calcd. for C H O (percent): C, 76.44; H. 7.90. Found (percent):C, 76.23; H, 7.95.

EXAMPLE 3 5 C/D-trans-3-[4,4 (2,3 naphthalenedioxy)pentyl]-6aflmethyl1,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta- [f] [1]benzopyran-7fi-ol Thecrude dienol ether (i)-3[4,4-(2,5-naphthalenedioxy) pentyl]-6afl methyl1,2,3,5,6,6a hexahydrocyclopenta[f] [1]benzopyran 7(8H) one (11.7 g.)dissolved in THF (120 ml.) was cooled to 5 and treated, dropwise withsodium-bis-(Z methoxyethoxy)aluminate (French Pat. 1,515,582) (7.1 ml.;70 percent w./w. in benzene). After stirring for a further 1 hr. at roomtemperature, ether (500 ml.) was added followed by dilute aqueous sodiumhydroxide solution (2 N; 100 ml.). The organic phase was washed withbrine and dried over MgSO Removal of the solvents in vacuo gave a glasscomprising racemic 3 [4,4 (2,3 naphthalenedioxy)- pentyl] 6a 8 methyl1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7fi-ol. This wasone major spot on the TLC analysis and showed bands in the LR. spectrum(CHCl solution) at 3600 and 3450 (OH), 1645 (dienol ether) and 1465 cm.(naphthalenedioxy).

The crude material (11.6 g.) was dissolved in THF (200 ml.) containing 5percent -Pd/C (1 g.) and bydrogenated at room temperature and pressureuntil one mole of hydrogen had been consumed. The solids were filteredoff washed well with more THF and the combined filtrates were taken todryness in vacuo to give product (11.7 g.) as a glass which contained amajor amount of C/D trans-3-[4,4 (2,3 naphthalenedioxy)pentyl]-6aB-methyl-1,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta[f][l] benzopyran-7p-ol.

This material was one major spot on TLC analysis and showed bands in theIR. spectrum (film) at 3450 (-OH), 1675 (enol ether) 1470 and 1250 cm.-(naphthalenedioxy). The NMR spectrum showed two methyl signals at 60.78p.p.m. in the ratio of approximately :15 indicating the relative amountsof C/D trans and C/D cis material respectively.

EXAMPLE 36 C/D-trans-3-[4,4-(4,5 dimethylphenylenedioxy)pentyl]-GaB-methyl-l,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta- [f] 1Jbenzopyran-7fi-ol Treatment of the dienol ether (i)-3-[4,4 (4,5dimethylphenylenedioxy)pentyl]-6afi-methyl1,2,3,5,6,6ahexahydrocyclopentafi][1]benzopyran-7(8H) one (9.8 g.) as inExample 35 yielded the crude alcohol racemic 3-[4,4-(4,5-dimethylphenylenedioxy)pentyl] -6afl methyl- 1,2,3,5,6,6a,7,8octahydrocyclopenta[f] [1]benzopyr'an- 718-01 ('10 g.) as a glass havingbands in the LR. spectrum at 3600 and 3450 (OH) and 1645 cm.- (dienolether). Hydrogenation asin Example 35 gave the enol ether C/D- 31 tran-3- [4,4-(4,5 dimethylphenylenedioxy)pentyl] 6aflmethyll,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta[f] [1] benzopyran-7 3-ol (10.4g.) as a glass.

The NMR spectrum showed the methyl signals centered at 60.74 ppm. in anapproximate ratio of 70:30 indicating the relative proportions of the C/D trans and C/ D cis materials respectively.

EXAMPLE 37 (i-)-6-[3,3-(2,3-naphthalenedioxy)butyl] 3afi methyl-4,5,8,9,9a,9/S-hexahydro-1H-benz[e]indene 3,7 (2H, 3aH)-dione A solutionof the crude enol ether C/D-trans-3- [4,4-(2,3-naphthalenedioxy)pentyl]-6afi-methyl 1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f] [1]benzopyran-7}8-ol (12.6 g.) in acetone (135ml.) was treated with dilute aqueous sulfuric acid (13.4 ml.; 1 N) andleft at room temperature [for 2 hrs. This solution of the crudehemiketal )-3-[4,4- (2,3-Iiaphthalenedioxy)butyl]-4-hydroxy-6a/3-methylperhydrocyclopenta[f] [1]benzopyran-7/3-ol Was then cooled to 5 andtreated over 20 min. with a solution of sodium dichromatesulfuric acid(34 ml.; from 100 g.

70.8 ml. H SO conc. made up to 250 ml. with water).

The mixture was then warmed to room temperature and stirred at thattemperature for a further 2 hrs. Dilute aqueous sodium bisulfitesolution was added (100 ml., 5 percent) followed by brine (100 ml.) andthe organic materials were isolated with benzene. The combined benzeneextracts were washed with an aqueous sodium carbonate solution (5percent; 2 40 ml.) dried over MgSO and taken to dryness in vacuo. Thisgave the triketone )-4- [3-oxo-7,7-(2,3-naphthalenedioxy)-octyl] lafimethylperhydroindan-1,5-dione (9.6 g.) as an orange colored oil showingbands in the IR. spectrum (CHCl solution) at 1740 (cyclopentanone), 1710(cyclohexanone and straight chain ketone) and 1470 cmr(naphthalenedioxy).

The crude triketone (9.6 g.), dissolved in methanol, was added to asolution of potassium hydroxide 1.44 g.) dissolved in more methanol (36ml.) and heated at reflux [for 1 /2 hrs. Glacial acetic acid (2.2 ml.)was added; the solvents were removed in vacuo and the residue wasextracted into methylene chloride, washed with brine, aqueous sodiumcarbonate solution (5 percent) and dried With MgS O Removal of thesolvents in vacuo yielded the crude tricyclic material as a brownpowder. Crystallization from chloroform-methanol mixture yielded pure(i)-6- [3,3-(2,3-naphthalenedioxy)-butyl]-3a;8 methyl 4,5,8,9,9a,9bhexahydro-1H-benz[e]indene-3,7-(2H,3aH) dione (3.9 g.), M.P.247249.

Analysis.Calcd. for C H O (percent): C, 78.12; H, 7.02. Found (percent):C, 77.81; H, 6.87.

EXAMPLE 3 8 )-6-[3,3-(4,5 dimethylphenylenedioxy)butyl] 3amethyl-4,5,8,9a,9b-hexahydro-1H-benz[e]-indene 3,7- (2H,3aHO)-dione Thecrude enol ether C/D-trans-3-[4,4-(4,5-dimethy1-phenylenedioxy)pentyl]-6a/3-methyl1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f] [1]benzopyran-7B-ol (10.4g.) in analogous fashion to Example 37 was hydrated to give the crudehemiketal (:)-3-[4,4 (4,5 dimethylphenylenedioxy)butyl]-4-hydroxy-6Bmethyl-perhydrocyclopenta[f] [1]benzopyran-7/3-ol. This compound wasoxidized as before to yield the crude triketone (:)-4-[3-oxo-7,7-(4,5-dimethylphenylenedioxy)octyl] 1a,8 methyl perhydroindan-l',5-dioneshowing bands in the LR. spectrum (CI-I Cl solution) at 1735(cyclopentanone), 1710 (cyclohexanone and straight chain ketone) and1485 cm.- (phenylenedioxy). Cyclization of the triketone yielded thecrude tricyclic material(i)-6-[3,3-(4,5-dimethylphenylenedioxy)butyl]Gap-methyl 4,5,8,9,9a,9bhexa-hydro- 32 1H-benz[e]-indene-3,7-(2H,3aH)-dione (4.7 g.) as anorange colored oil. Chromatography on g. of silica gel usingbenzene-ethyl acetate mixture (9:1 and 17:3) followed by crystallizationfrom ethanol gave pure product (1.37 g.), M.P. 164-165.

Analysis.Calcd. for C H O (percent): C, 76.44; H, 7.90. Found (percent):C, 76.20; H, 7.75.

EXAMPLE 39 )-6-[3,3-(2,3-naphthalenedioxy)butyl] 3aflmethylperhydrobenz[e]-iudane-3,l7-dione The tricyclic material(i-)-6-[3,3-(2,3-naphthalenedioxy)butyl]-3a,B-methyl-4,5,9,9a,9bhexahydro-l'H-benz- [e]indene-3,7-(2H,3aH)-dione (3.2 g.) was treatedwith 5 percent Pd/C (500 mg.) in THE (100 ml.) containing triethylamine(1 ml.) and hydrogenated at room temperature and pressure until one moleof hydrogen had been consumed. The solids were filtered 011 and thesolvents removed in vacuo. Crystallization of a sample from ethanolyielded the saturated diketone, M.P. 190-195 Analysis.Calcd. for C H O(percent): C, 77.75; H, 7.46. Found (percent): C, 77.92; H, 7.32.

EXAMPLE 4O )-19-nor-androst-4-ene-3,17-dione (A) A solution of(i-)-6-[3,3-(2,3-naphthalenedioxy) butyl] -3a/i-methyl-perhydrobenz[e]-indane-3,17-dione (2 g.) in n-butanol (60ml.) was treated with dilute aqueous hydrochloric acid (20 mL; 4 N) andheated at reflux for 4 hrs. The solvents were removed in vacuo and theresidue was extracted with ether. After washing the ethereal solutionwith aqueous sodiu m carbonate solution (10 percent) and caustic sodasolution (1 N) the solvents were removed in vacuo. Crystallization ofthe residue from methylene chloride-isopropyl ether mixture yieldedracemic l9-norandrost-4-ene-3,l7-dione (1.06 g.), MJP. -156 identicalwith authentic material (TLC; I.R., U.V.).

U.V. A 239 m 17,100); LR. bands at 1738 (cyclopentanone) 1665 and 1620cm.- (cyclohexenone).

'(B) A solution of (i)-6-[3,3-(4,5-dimethylphenylenedioxy)butyl] 321pmethyl 4,5,'8,9a,9b -hexahydro-1H- benz[e]-indene-3,7-(2H,3aH)-dione(1.22 g.) in THF (50 ml.) containing triethylamine (.5 ml.) and 5percent Pd/C (300 mg.) was hydrogenated at room temperature and pressureuntil one mole of hydrogen was consumed. The solids were filtered'oifand the filtrate was taken to dryness in vacuo. The residue (1.3 g.),consisting of (i)- 6-[3,3-(4,5-phenylenedioxy)butyl] 3a;3methyl-perhydrobenz[e]indane-3,17-dione which showed bands in the LR.t(CHCl solution) at 1735 cyclopentanone), 1705 (cyclohexanone) and 1485cm.- (phenylenedioxy), dissolved in ethanol (30 ml.) was treated withdilute aqueous hydrochloric acid (4 N; 10 ml.) and heated under refluxfor 4 hrs. Removal of the solvents in vacuo and workup as before yielded(i)-19-nor-androst-4-ene-3,17-dione (615 mg.) on crystallization frommethylene chloride-isopropyl ether mixture.

This material was again identical with authentic material (M.P., mixedM.P.;TLC, I.R., and U.V. spectra).

U.V. A 239 mp (e 17,000); I.R. showed bands at 1738 (cyclopentanone),1665 and 1620 cm.- (cyclohexenone).

We claim:

1. A compound of the formula B is the remaining residue of a phenyleneor naphthalene group and which may bear one or two additionalsubstitnents selected from the group consisting of lower alkyl or loweralkoxy; R R R R and R are each independently hydrogen or lower alkyl; Vis hydrogen, lower alkyl or lower acyl; R is chloro, hydroxy, loweralkoxy, lower hydrocarbylamino or di(lower hydrocarbyl)amino; and R islower hydrocarbylamino or di(lower hydrocarbyl) amino and the opticalenantiomers, tautomers and acid addition salts thereof.

2. The compound of claim 1 wherein V is hydrogen and R is lowerhydrocarbylamino or di(lower hydrocarbyDamino and tautomers thereof.

3. The compound of claim 2 wherein R is diethylamino and Y is selectedfrom the group consisting of 3,3 (phenylenedioxy)'butyl;3,3-(2,3-naphthalenedioxy)- butyl and3,3-(4,S-dimethylphenylenedioxy)-butyl.

4. The compound of claim 2 wherein R is an optically active amino group.

5. The compound of claim 4 wherein R is selected from the groupconsisting of R-wphenethylamino and S- a-phenethylamino.

6. The compound of claim 5 wherein R is R-a-phenethylamino and Y is3,3-(phenylenedioxy)-butyl.

7. The compound of claim 5 wherein R is S-u-phenethylamino and Y is3,3-(phenylenedioxy)-butyl.

8. The compound of claim 1 wherein R R R R and R are each independentlyhydrogen.

9. The compound of claim 8 wherein R is diethylamino and Y is3,3-(phenylenedioxy)=butyl,

10. The compound of claim 8 wherein R is diethylamino and Y is3,3-(naphthylenedioxy)-butyl.

11. The compound of claim 8 wherein R is diethylamino and Y is3,3-(4,S-dimethyl-phenylenedioxy)-butyl.

References Cited UNITED STATES PATENTS 3,048,599 8/ 1962 Rosenmund eta]. 260-3435 ALEX MAZEL, Primary Examiner I. H. TURNIPS'EED, AssistantExaminer US. Cl. X.R. 260-3435, 397.4

